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Preoperative Testing For Lynch Syndrome Yields ‘Huge’ Benefit


Preoperative Testing For Lynch Syndrome Yields ‘Huge’ Benefit

Vancouver, British Columbia—Mayo Clinic researchers are calling for all young patients with colorectal cancer (CRC) to undergo preoperative testing for Lynch syndrome as the results can significantly alter surgical management.

“The benefit of this testing to the patient and their family is huge,” said Rajesh Pendlimari, MBBS, a research fellow at Mayo Clinic in Rochester, Minn., and a study investigator.

“If they have Lynch syndrome and will, therefore, be more prone to getting cancer, they can get screened more regularly. The knowledge gleaned can change the course of surgical treatment.”

At the 2011 annual meeting of the American Society of Colon and Rectal Surgeons, the Mayo team presented two studies examining the benefit of pre- and postoperative microsatellite instability (MSI) testing for Lynch syndrome.

In the first study, 210 of 258 newly diagnosed patients younger than age 50 years who underwent colorectal surgery at Mayo Clinic had MSI testing between 2003 and 2008. Of these, 82 underwent testing postoperatively, according to the hospital’s protocol requiring pathologists to complete MSI testing on operative specimens for all young patients who did not have the tests done prior to surgery. Overall, 13% of patients were found to have high levels of MSI and 33% of these would have been missed without the testing protocol.

The second, complementary paper retrospectively compared the surgical management of 210 patients who were tested pre- and postoperatively for MSI (n=103, n=107, respectively). (The number of patients in the postoperative group differs in the two studies: It is listed as 82 in the first study and 107 in the second because 25 patients underwent preoperative testing on the day of surgery; their results were not available to surgeons before operating.)

Results showed that the MSI test results significantly influenced surgical recommendations for total colectomy. Of patients with positive preoperative MSI tests (MSI-H), 94% underwent total colectomy, compared with 8% of patients whose status was not known until after surgery (P<0.0001). Moreover, there appears to be an increased rate of hysterectomy among women with MSI-H. Eight of 10 MSI-H women had a hysterectomy. There was only one female patient who was tested postoperatively and she did not have a hysterectomy.

“Probably the most significant result of this research is that it has stimulated our multidisciplinary team of geneticists, pathologists, gastroenterologists and surgeons to develop new clinical pathways that will direct patients at risk to providers experienced with management of Lynch syndrome,” said Eric Dozois, MD, professor of surgery at Mayo Clinic and lead researcher on the project.

Other gastroenterologists and surgeons applauded the paper, saying that preoperative testing for Lynch syndrome is easy to do and can dramatically affect surgical treatment.

“Virtually everybody [who] gets an operation for colorectal cancer has a colonoscopy or biopsy of the tumor before they go on to surgery. In my opinion, that is a golden opportunity, since you are taking a biopsy anyway, to get the cascade of evaluation going for the possible presence of HNPCC [hereditary nonpolyposis colorectal cancer],” said Patrick Lynch, MD, professor of medicine in the Department of Gastroenterology, Hepatology and Nutrition at the University of Texas MD Anderson Cancer Center in Houston.

He added that endoscopists should not skip the opportunity for testing during colonoscopic biopsy.

“It doesn’t take that much material, it’s easy to do and you’re doing it at the front end of a window of opportunity that exists between that time and when the patient goes to surgery. The surgeon and the patient can use that information to decide if they want to expand the surgery from a simple segmental resection to a subtotal colectomy.”

Preoperative testing could improve treatment for younger patients, a group that is showing increased incidence of CRC, said Michael Stamos, MD, professor and chair of surgery at the University of California, Irvine, where surgeons and gastroenterologists routinely do immunohistochemistry (IHC) staining testing prior to surgery.

The Mayo Clinic team has developed a new clinical pathway (Figure) for testing and treatment of patients at high risk for CRC. The protocol requires all high-risk patients to undergo either MSI or IHC to test for Lynch syndrome prior to surgery.

It’s still unclear which test is best to start with. Although MSI is the gold standard test for the DNA mismatch repair, it does have some disadvantages such as a slow turnaround time and it requires an advanced and experienced lab as well as more testing than IHC. Individuals with positive results still need to undergo IHC. On the other hand, IHC requires an experienced pathologist and detects abnormalities of only four major genes.

The best test depends on the local expertise, said Dr. Stamos.

Of every 35 patients with CRC, one has Lynch syndrome, the most common hereditary cause of colorectal and endometrial cancers.

The last guideline on screening was the 2004 Revised Bethesda Guideline, which calls for MSI screening for anyone with young-onset (<50 years old) CRC, synchronous or metachronous CRC or HNPCC-associated cancer at any age, CRC in a patient under age 60 years with tumor-infiltrating T lymphocytes, mucinous/signet ring differentiation or Crohn’s-like lymphocytic reaction, or for patients of any age with a first-degree relative with an HNPCC-related tumor before age 50, or two first- or second-degree relatives with HNPCC tumors at any age.

“Since those guidelines, we’ve discovered a new gene,” said Dr. Pendlimari. “Our understanding of this disease is changing considerably.”

Inherited predisposition to colorectal cancer in patients without multiple polyps


 

Lynch Syndrome / Hereditary non-polyposis colorectal cancer (HNPCC) and related syndromes

Lynch Syndrome (also known as Hereditary non-polyposis colorectal cancer(HNPCC; OMIM 120435)) accounts for approximately 2.2-4% of all colorectal cancer (Hampel et al. 2005).  Lynch Syndrome is a familial cancer syndrome which accounts for approximately 2-3% of all colorectal cancer in the UK.  It has formerly been known as Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), however the phenotype is more complex with multiple extracolonic tumours, for example, so this term has now been largely abandoned.

An Irish family tree with Lynch Syndrome caused by an inherited mutation in MSH2.  Members of this family are affected predominantly with colorectal cancer (CRC), but also small bowel cancer (SBCa), Gastric, Pancreatic, Uterine and other cancers, as well as conditions not linked to Lynch Syndrome such as Crohn’s disease.

LS is an autosomally dominant inherited condition commonly caused by germline mutation in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6 and PMS2.  A minority of these families may be identified because they have multiple affected members diagnosed at an early age.   The Amsterdam Criteria I and II (Vasen et al. 1993; Vasen et al. 1999)(see below) identify patients for colonoscopic and other screening.  Approximately 40-80% of patients meet these criteria, with 50% of the remainder meeting the modified criteria which include extracolonic cancers.  The revised Bethesda criteria (Umar et al. 2004) are used to identify patients for molecular screening of HNPCC, i.e. microsatellite instability ± immunohistochemistry studies.  Approximately 80% of patients are identified using the Bethesda criteria, although the specificity is low.

Immunohistochemistry and microsatellite instability analysis for Lynch Syndrome

Amsterdam I Criteria

  • ≥3 1st degree relatives with colorectal cancer (CRC)
  • ≥2 generations affected
  • One family member below age 50 years of age
  • Exclude familial adenomatous polyposis

Amsterdam II Criteria

  • As for Amsterdam I except that CRC may be substituted by cancer of endometrium, small bowel, or pelviureter.

Most families with LS, however, do not fulfil the Amsterdam criteria. The Revised Bethesda criteria are another set of diagnostic criteria designed to increase the diagnostic yield of testing for LS [7]. For example, all individuals diagnosed under the age of 50 years should be tested for the molecular features of LS in their tumours.  If molecular testing is diagnostic of LS, it can subsequently determine which families should undergo colonoscopic and other investigations, and to screen other high risk family members. The Revised Bethesda guidelines are designed to streamline the clinical diagnostic pathways used to identify mutation carriers in patients with colorectal cancer who might or might not fulfil the Amsterdam criteria, thus increasing diagnostic yield screening for LS.

The identification of such families with Lynch syndrome involves an extensive diagnostic work up comprising various screening tools combined with genetic and immunohistochemical tests.  Initially the tumour from an affected individual may be tested for features suggestive of this condition by either immunohistochemistry of the mismatch repair proteins and/or DNA microsatellite instability (a hallmark of faulty DNA mismatch repair).  If either of these tests are abnormal, then germline testing may be performed to identify a putative heritable mutation in one of the causative genes.

Patient selection using Amsterdam and revised Bethesda criteria have been applied to clinical pathways in the United Kingdom through the use of national guidelines.  Given the implication of family history and known mortality benefit, the early recognition of Lynch syndrome is highly desirable. There have been concerns over the sensitivity, specificity, and predictive value of already existing guidelines. About 22% of affected individuals do not fulfil either Amsterdam or the Revised Bethesda criteria. As Barnetson et al argues, there might be multiple reasons for this such as small family size, unknown or inadequately taken family history, adoption, and patients without available tumour data [9]. A number of alternative screening models have been developed, such as MMRpredict, PREMM 1,2,6, MMRPro, and MsPath whilst searching for a careening tool that is simple, accurate, and clinically useful for predicting the likelihood of Lynch Syndrome.

Bethesda (revised) Criteria (Umar et al 2003)

  • 1 CRC below age 50 yr
  • Multiple CRC or HNPCC-related cancers
  • CRC with MSI-related histology under 60 years of age
  • CRC or HNPCC-related cancer in ≥1 1st degree relative, < 50 years of age
  • CRC or HNPCC-related cancer in at least two 1st or 2nd degree relatives, any age

MSI-type Histology: Using the revised Bethesda Criteria patients aged 50-60 years should have tumour testing

There is a slight preponderance of right-sided tumours (70% proximal to the splenic flexure) in Lynch Syndrome.  It is a highly penetrant condition which also features extracolonic cancers such as endometrial and gastric cancer.  The adenoma to carcinoma sequence is rapid with interval cancers occurring in 5% of patients despite two-yearly colonoscopic surveillance (Jarvinen, Aarnio et al. 2000).  The tumours are characteristically associated with a local lymphocytic infiltrate and a good prognosis when surgically resected (Jass 2000; Takemoto et al. 2004).

Screening tumours for Lynch Syndrome – is it cost effective?

There are clinical and economic trade-offs when implementing screening protocol on a large scale. As nondirected germline mutation testing for Lynch syndrome is prohibitively expensive at £1000 per gene, MSI and IHC are the screening tests of choice. In view of high costs of testing of all colorectal cancers for MSI or loss or MMR protein, an approach described by Heather Hampel of The Ohio State University, the Revised Bethesda Guidelines were felt to be an appropriate tool to select patients for genetic testing. However, the question remains open: is the “reflex” molecular tumour testing justified clinically and economically? Kastrinos et al, have looked into the popularity of the universal testing across several centres in US. Unsurprisingly, a pessimistic picture emerged showing the low uptake of the concept. The benefits of the universal testing are counterbalanced by practical problems such as an informed consent controversy, practicalities of dealing with the complexity of test results and the resultant implications. The fact that the cost effectiveness of this approach has not been yet validated plays heavily against such approach.

In US, Ramsey et al have carried out a study looking at cost-effectiveness of different strategies for identifying of persons with Lynch syndrome. The average cost per carrier detected using Bethesda guidelines was $15,787, and expanding this strategy to include costs and benefits for first degree relatives greatly improves the cost effectiveness of the program. Expanding the program to first degree relatives leads to savings from intensive screening to exceed the cost of testing.

In Europe, Pinol et al, has carried out a similar study evaluating cost-minimization analysis of identification strategies for MSH2/MLH1-associated Lynch syndrome. Authors concluded that clinical selection of patients using the Revised Bethesda Guidelines followed by either MSI analysis (€11,989 per detected mutation) or IHC (€10,644 per detected mutation) has proved to be more cost effective than performing any of these tests directly (€32,140 and €37,956 per detected mutation, respectively).

Further research has been carried out by Dinh et al in 2010 looking at the cost effectiveness of MMR gene mutations screening, and reached the conclusion that it is comparable to that of already established cancer screening protocols such as colorectal, cervical, and breast cancer screening. Authors argue that primary screening of individuals for MMR gene mutations, starting with the risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost effective manner relative to current practise with the average cost-effectiveness ratio of $26,000 per QALY.

These results echo several European studies, such as that carried out by Pinol V et al, 2005 in Spain, where authors suggest that MSI and IHC testing are equivalent strategies in terms of cost effectiveness when it comes to screening selected patients for MMR mutations

Large bowel surveillance for Lynch syndrome family members and gene carriers

Total colonic surveillance (at least biennial) should commence at age 25 years. Surveillance colonoscopy every 18 months may be appropriate because of the occurrence of interval cancers in some series.  Surveillance should continue to age 7075 years or until co-morbidity makes it clinically inappropriate. If a causative mutation is identified in a relative and the consultand is a non-carrier, surveillance should cease and measures to counter general population risk should be applied.

The effectiveness of colonoscopic surveillance for people with MMR gene mutations and Lynch family members has been examined in retrospective casecontrol comparisons. Screened individuals were compared to control subjects who declined, or did not receive, regular colonoscopy with respect to outcomes of cancer incidence, tumour stage and mortality, or mortality alone. Surveillance appears to provide an average of 7 years of extra life for Lynch syndrome family members.  Thus, available evidence supports regular colonoscopic surveillance as a means of early colorectal cancer detection, leading to mortality reduction as well as reduction in cancer incidence.

Surveillance should consist of total colonoscopy, since the risk of polyps and cancer is high and a substantial proportion of patients have neoplasia restricted to the proximal colon.  Colonoscopy is preferable to flexible sigmoidoscopy combined with barium enema. Because the cancer risk is high, it is not appropriate to accept an incomplete colonoscopy until the next surveillance interval. Incomplete colonoscopy should be followed soon after, or even the same day, by completion CT colonography in centres skilled in providing this technique to a high quality, but repeated radiation exposure should be avoided wherever possible. Repeat full colonoscopy or barium enema remain as options. Chromoendoscopy and narrow wavelength visible light (narrow band) endoscopy may have a place in the detection of small or flat lesions, but there is very limited experience and evidence is restricted to descriptive studies of their use in Lynch syndrome surveillance. Hence, the utility of such techniques requires further assessment and is neither recommended nor discouraged in high risk surveillance, but should not replace conventional endoscopic approaches. Evidence for commencing surveillance at 25 years of age is based on observational data that indicate that the risk increases substantially from age 25 in groups defined by family history and in groups defined by presence of a mutation.

Colorectal resection has a place as prophylaxis and for established cancer in Lynch syndrome family members and/or MMR gene carriers.

Patients who have developed a colorectal malignancy and who come from a Lynch syndrome family, or carry a mutation in an MMR gene, should be counselled and offered a surgical procedure that includes both a cancer control element and prophylaxis to counter future cancer risk. At present there is no evidence to guide decision-making on primary prophylactic surgery for patients who do not yet have cancer.

People with MMR gene mutations or those from Amsterdam positive Lynch syndrome families who have cancer will require surgery unless treatment is palliative. Case series evidence shows that the risk of metachronous colorectal cancer is high following segmental resection (16%), but substantially lower after colectomy and ileorectal anastomosis (3%).  Hence, incorporating a prophylactic element to the cancer resection is appropriate. For patients with proximal tumours, colectomy and ileorectal anastomosis is most relevant, but the retained rectum must be screened because cancer risk in the retained rectum is 3% every 3 years for the first 12 years.

Upper gastrointestinal surveillance for Lynch syndrome family members and/or MMR gene carriers

In families manifesting gastric cancer as part of the phenotype, biennial upper gastrointestinal endoscopy should be considered. The evidence is limited and a pragmatic recommendation is to screen from age 50 since the incidence is very low until that age. Surveillance should continue to age 75 or until the causative mutation in that family has been excluded. This recommendation is based on observations that some Lynch syndrome families have a particular propensity for gastric cancer.  There is as yet no evidence that this reduces mortality.

Other non-polyposis predisposition to colorectal neoplasia

About 15% of sporadic colorectal cancers are also microsatellite unstable and feature loss of protein staining on immunohistochemistry but are not caused by germline mutations in mismatch repair genes.  Often they are acquired sporadic type cancers caused by methylation of MLH1.  These associated with a particular genetic pathway which differs from HNPCC by the presence of BRAF V600E mutations, the absence of β-CATENIN exon 3 mutations and a methylator genotype (Young et al. 2005) (Oliveira et al. 2005).  Recently kindreds demonstrating some inheritance of MLH1 promoter methylation have been identified (Suter et al. 2004; Hitchins, Williams et al. 2005), although the evidence for this inherited epimutation is limited to a few case studies and may be related in imprinting (Chong et al. 2007; Hitchins and Ward 2007).

In addition there are a number of families which fulfil Amsterdam criteria but do not demonstrate microsatellite instability (Dove-Edwin, de Jong et al. 2006).  These families are termed by one group familial colorectal cancer type X (Lindor et al. 2005), and have a lower incidence of colorectal cancer occurring at a later age.  The genetic aetiology is not known for these families.

Approximately 93% of colorectal cancer occurs after the age of 50 years, and thus those young patients who develop cancer are likely to have an inherited or other risk factor such as chronic colitis.  The genetic risk is partially made up by inherited mutations which cause HNPCC.  However, there are likely to be a number of other lower penetrance genes which cause cancer predisposition, many of which may have a recessive form of inheritance and few polyps, and therefore a less clearly identifiable phenotype.

 

Lynch Syndrome and other non-polyposis inherited cancer syndromes


Lynch Syndrome / Hereditary non-polyposis colorectal cancer (HNPCC) and related syndromes

Lynch Syndrome (OMIM 120435)) is a familial cancer syndrome which accounts for approximately 2.2-4% of all colorectal cancer in the USA (Hampel et al. 2005) and 2-3% of the total in the UK.  It was also known as Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), however the phenotype is more complex with multiple extracolonic tumours, for example, so this term has now been largely abandoned.

An Irish family tree with Lynch Syndrome caused by an inherited mutation in MSH2.  Members of this family are affected predominantly with colorectal cancer (CRC), but also small bowel cancer (SBCa), Gastric, Pancreatic, Uterine and other cancers, as well as conditions not linked to Lynch Syndrome such as Crohn’s disease.

LS is an autosomally dominant inherited condition commonly caused by germline mutation in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6 and PMS2, involved with the mismatch repair (MMR) pathway. This pathway functions to identify and remove single nucleotide mismatches or insertions and deletion loops. Mutations in four of the MMR genes can cause Lynch syndrome [Peltomaki 2003]. The functions of the mismatch repair genes can be disrupted by missense mutations, truncating mutations, splice site mutations, large deletions, or genomic rearrangements. In addition, germline deletion within EPCAM, which is not an MMR gene, can disrupt the MMR pathway. EPCAM deletions result in inactivating the adjacent MMR gene MSH2, even though MSH2 itself has not been mutated.

Identification of LS Families

A minority of Lynch Syndrome families may be identified because they have multiple affected members diagnosed at an early age.   The Amsterdam Criteria I and II (Vasen et al. 1993; Vasen et al. 1999)(see below) identify patients for colonoscopic and other screening.  Approximately 40-80% of patients meet these criteria, with 50% of the remainder meeting the modified criteria which include extracolonic cancers.  The revised Bethesda criteria (Umar et al. 2004) are used to identify patients for molecular screening of HNPCC, i.e. microsatellite instability ± immunohistochemistry studies.  Approximately 80% of patients are identified using the Bethesda criteria, although the specificity is low.

Immunohistochemistry and microsatellite instability analysis for Lynch Syndrome

Amsterdam I Criteria

  • ≥3 1st degree relatives with colorectal cancer (CRC)
  • ≥2 generations affected
  • One family member below age 50 years of age
  • Exclude familial adenomatous polyposis

Amsterdam II Criteria

  • As for Amsterdam I except that CRC may be substituted by cancer of endometrium, small bowel, or pelviureter.

Most families with LS, however, do not fulfil the Amsterdam criteria. The Revised Bethesda criteria are another set of diagnostic criteria designed to increase the diagnostic yield of testing for LS [7]. For example, all individuals diagnosed under the age of 50 years should be tested for the molecular features of LS in their tumours.  If molecular testing is diagnostic of LS, it can subsequently determine which families should undergo colonoscopic and other investigations, and to screen other high risk family members. The Revised Bethesda guidelines are designed to streamline the clinical diagnostic pathways used to identify mutation carriers in patients with colorectal cancer who might or might not fulfil the Amsterdam criteria, thus increasing diagnostic yield screening for LS.

The identification of such families with Lynch syndrome involves an extensive diagnostic work up comprising various screening tools combined with genetic and immunohistochemical tests.  Initially the tumour from an affected individual may be tested for features suggestive of this condition by either immunohistochemistry of the mismatch repair proteins and/or DNA microsatellite instability (a hallmark of faulty DNA mismatch repair).  If either of these tests are abnormal, then germline testing may be performed to identify a putative heritable mutation in one of the causative genes.

Patient selection using Amsterdam and revised Bethesda criteria have been applied to clinical pathways in the United Kingdom through the use of national guidelines.  Given the implication of family history and known mortality benefit, the early recognition of Lynch syndrome is highly desirable. There have been concerns over the sensitivity, specificity, and predictive value of already existing guidelines. About 22% of affected individuals do not fulfil either Amsterdam or the Revised Bethesda criteria. As Barnetson et al argues, there might be multiple reasons for this such as small family size, unknown or inadequately taken family history, adoption, and patients without available tumour data [9]. A number of alternative screening models have been developed, such as MMRpredict, PREMM 1,2,6, MMRPro, and MsPath whilst searching for a careening tool that is simple, accurate, and clinically useful for predicting the likelihood of Lynch Syndrome.

Bethesda (revised) Criteria (Umar et al 2003)

  • 1 CRC below age 50 yr
  • Multiple CRC or HNPCC-related cancers
  • CRC with MSI-related histology under 60 years of age
  • CRC or HNPCC-related cancer in ≥1 1st degree relative, < 50 years of age
  • CRC or HNPCC-related cancer in at least two 1st or 2nd degree relatives, any age

MSI-type Histology: Using the revised Bethesda Criteria patients aged 50-60 years should have tumour testing

There is a slight preponderance of right-sided tumours (70% proximal to the splenic flexure) in Lynch Syndrome.  It is a highly penetrant condition which also features extracolonic cancers such as endometrial and gastric cancer.  The adenoma to carcinoma sequence is rapid with interval cancers occurring in 5% of patients despite two-yearly colonoscopic surveillance (Jarvinen, Aarnio et al. 2000).  The tumours are characteristically associated with a local lymphocytic infiltrate and a good prognosis when surgically resected (Jass 2000; Takemoto et al. 2004).

Screening tumours for Lynch Syndrome – is it cost effective?

There are clinical and economic trade-offs when implementing screening protocol on a large scale. As nondirected germline mutation testing for Lynch syndrome is prohibitively expensive at £1000 per gene, MSI and IHC are the screening tests of choice. In view of high costs of testing of all colorectal cancers for MSI or loss or MMR protein, an approach described by Heather Hampel of The Ohio State University, the Revised Bethesda Guidelines were felt to be an appropriate tool to select patients for genetic testing. However, the question remains open: is the “reflex” molecular tumour testing justified clinically and economically? Kastrinos et al, have looked into the popularity of the universal testing across several centres in US. Unsurprisingly, a pessimistic picture emerged showing the low uptake of the concept. The benefits of the universal testing are counterbalanced by practical problems such as an informed consent controversy, practicalities of dealing with the complexity of test results and the resultant implications. The fact that the cost effectiveness of this approach has not been yet validated plays heavily against such approach.

In US, Ramsey et al have carried out a study looking at cost-effectiveness of different strategies for identifying of persons with Lynch syndrome. The average cost per carrier detected using Bethesda guidelines was $15,787, and expanding this strategy to include costs and benefits for first degree relatives greatly improves the cost effectiveness of the program. Expanding the program to first degree relatives leads to savings from intensive screening to exceed the cost of testing.

In Europe, Pinol et al, has carried out a similar study evaluating cost-minimization analysis of identification strategies for MSH2/MLH1-associated Lynch syndrome. Authors concluded that clinical selection of patients using the Revised Bethesda Guidelines followed by either MSI analysis (€11,989 per detected mutation) or IHC (€10,644 per detected mutation) has proved to be more cost effective than performing any of these tests directly (€32,140 and €37,956 per detected mutation, respectively).

Further research has been carried out by Dinh et al in 2010 looking at the cost effectiveness of MMR gene mutations screening, and reached the conclusion that it is comparable to that of already established cancer screening protocols such as colorectal, cervical, and breast cancer screening. Authors argue that primary screening of individuals for MMR gene mutations, starting with the risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost effective manner relative to current practise with the average cost-effectiveness ratio of $26,000 per QALY.

These results echo several European studies, such as that carried out by Pinol V et al, 2005 in Spain, where authors suggest that MSI and IHC testing are equivalent strategies in terms of cost effectiveness when it comes to screening selected patients for MMR mutations

Large bowel surveillance for Lynch syndrome family members and gene carriers

Total colonic surveillance (at least biennial) should commence at age 25 years. Surveillance colonoscopy every 18 months may be appropriate because of the occurrence of interval cancers in some series.  Surveillance should continue to age 7075 years or until co-morbidity makes it clinically inappropriate. If a causative mutation is identified in a relative and the consultand is a non-carrier, surveillance should cease and measures to counter general population risk should be applied.

The effectiveness of colonoscopic surveillance for people with MMR gene mutations and Lynch family members has been examined in retrospective casecontrol comparisons. Screened individuals were compared to control subjects who declined, or did not receive, regular colonoscopy with respect to outcomes of cancer incidence, tumour stage and mortality, or mortality alone. Surveillance appears to provide an average of 7 years of extra life for Lynch syndrome family members.  Thus, available evidence supports regular colonoscopic surveillance as a means of early colorectal cancer detection, leading to mortality reduction as well as reduction in cancer incidence.

Surveillance should consist of total colonoscopy, since the risk of polyps and cancer is high and a substantial proportion of patients have neoplasia restricted to the proximal colon.  Colonoscopy is preferable to flexible sigmoidoscopy combined with barium enema. Because the cancer risk is high, it is not appropriate to accept an incomplete colonoscopy until the next surveillance interval. Incomplete colonoscopy should be followed soon after, or even the same day, by completion CT colonography in centres skilled in providing this technique to a high quality, but repeated radiation exposure should be avoided wherever possible. Repeat full colonoscopy or barium enema remain as options. Chromoendoscopy and narrow wavelength visible light (narrow band) endoscopy may have a place in the detection of small or flat lesions, but there is very limited experience and evidence is restricted to descriptive studies of their use in Lynch syndrome surveillance. Hence, the utility of such techniques requires further assessment and is neither recommended nor discouraged in high risk surveillance, but should not replace conventional endoscopic approaches. Evidence for commencing surveillance at 25 years of age is based on observational data that indicate that the risk increases substantially from age 25 in groups defined by family history and in groups defined by presence of a mutation.

Colorectal resection has a place as prophylaxis and for established cancer in Lynch syndrome family members and/or MMR gene carriers.

Patients who have developed a colorectal malignancy and who come from a Lynch syndrome family, or carry a mutation in an MMR gene, should be counselled and offered a surgical procedure that includes both a cancer control element and prophylaxis to counter future cancer risk. At present there is no evidence to guide decision-making on primary prophylactic surgery for patients who do not yet have cancer.

People with MMR gene mutations or those from Amsterdam positive Lynch syndrome families who have cancer will require surgery unless treatment is palliative. Case series evidence shows that the risk of metachronous colorectal cancer is high following segmental resection (16%), but substantially lower after colectomy and ileorectal anastomosis (3%).  Hence, incorporating a prophylactic element to the cancer resection is appropriate. For patients with proximal tumours, colectomy and ileorectal anastomosis is most relevant, but the retained rectum must be screened because cancer risk in the retained rectum is 3% every 3 years for the first 12 years.

Upper gastrointestinal surveillance for Lynch syndrome family members and/or MMR gene carriers

In families manifesting gastric cancer as part of the phenotype, biennial upper gastrointestinal endoscopy should be considered. The evidence is limited and a pragmatic recommendation is to screen from age 50 since the incidence is very low until that age. Surveillance should continue to age 75 or until the causative mutation in that family has been excluded. This recommendation is based on observations that some Lynch syndrome families have a particular propensity for gastric cancer.  There is as yet no evidence that this reduces mortality.

Other non-polyposis predisposition to colorectal neoplasia

About 15% of sporadic colorectal cancers are also microsatellite unstable and feature loss of protein staining on immunohistochemistry but are not caused by germline mutations in mismatch repair genes.  Often they are acquired sporadic type cancers caused by methylation of MLH1.  These associated with a particular genetic pathway which differs from LS by the presence of BRAF V600E mutations, the absence of β-CATENIN exon 3 mutations and a methylator genotype (Young et al. 2005) (Oliveira et al. 2005).  Recently kindreds demonstrating some inheritance of MLH1 promoter methylation have been identified (Suter et al. 2004; Hitchins, Williams et al. 2005), although the evidence for this inherited epimutation is limited to a few case studies and may be related in imprinting (Chong et al. 2007; Hitchins and Ward 2007).

In addition there are a number of families which fulfil Amsterdam criteria but do not demonstrate microsatellite instability (Dove-Edwin, de Jong et al. 2006).  These families are termed by one group familial colorectal cancer type X (Lindor et al. 2005), and have a lower incidence of colorectal cancer occurring at a later age.  The genetic aetiology is not known for these families.

Approximately 93% of colorectal cancer occurs after the age of 50 years, and thus those young patients who develop cancer are likely to have an inherited or other risk factor such as chronic colitis.  The genetic risk is partially made up by inherited mutations which cause HNPCC.  However, there are likely to be a number of other lower penetrance genes which cause cancer predisposition, many of which may have a recessive form of inheritance and few polyps, and therefore a less clearly identifiable phenotype.

Colorectal Cancer Aetiology


 

Epidemiology

 

Colorectal cancer is diagnosed in approximately 35,000 people in the United Kingdom each year, the third most commonly diagnosed cancer after breast and lung cancer (NICR 2005; ONS 2005, ISD_Online, 2005 #540).  With 16,148 deaths in 2004 it was the second most common-cause of cancer death.  This is also true in other Caucasian populations (Jemal et al. 2007).

Age-standardised death rates from Colon and re...

Age-standardised death rates from Colon and rectum cancers by country (per 100,000 inhabitants). (Photo credit: Wikipedia)

Colorectal cancer, however,is not equally common throughout the world (Boyle and Langman 2000).  In the ‘westernised’countries colorectal cancerrepresents ~13.4% of all incident cases compared to ~7.8% elsewhere.

The occurrence of colorectal cancer is strongly related to age, with 93% occurring after the age of 50 years (ONS 2005).  Before this age there are equal numbers of males and females diagnosed, although after males predominate, with an eventual overall male to female ratio of 1.2:1.  Using data for England and Wales the overall lifetime risk of colorectal cancer is 1 in 18 for men and 1 in 20 for women (CRUK. 2006).  Sixty two percent of cancers are situated in the colon and the remainder in the rectum (ONS 2005).  Seventy percent are left-sided and the remainder right-sided (Toms 2004).

English: Gross appearance of an opened colecto...

Gross appearance of an opened colectomy specimen containing an invasive colorectal carcinoma and two adenomatous polyps. (Photo credit: Wikipedia)

More than 90% of colorectal cancers are adenocarcinomas arising from benign precursor adenomas.  A small proportion may arise from other types of polyps including hyperplastic and serrated polyps (Young et al. 2007).  The remainder of colorectal malignant tumours include carcinoids and lymphomas.  The National Polyp Study showed that endoscopic removal of adenomas prevents colorectal cancer (Winawer et al. 1993).  Endoscopic surveillance and polyp removal is a vital tool making colorectal cancer also one of the most preventable cancers as polyps removed at an early stage can prevent the cancer ever occurring.   Of course the endoscopic procedure performed must be technically perfect, performed at the correct stage in cancer development and in appropriate groups, e.g. for age, risk etc.  The resources are not available to perform colonoscopy on whole populations.  Identifying individuals at high risk due to genetic or environmental factors will help us undertake these preventative measures with the highest levels of efficacy and efficiency.

The concordance rates of cancer in monozygous and dizygous twins suggest that about one-third of the variation in cancer risk might typically be ascribed to genetic factors (Lichtenstein et al. 2000).  Highly penetrant (Mendelian) genetic syndromes account for 5–10% (Cannon-Albright et al. 1988) (Houlston et al. 1992) (Johns and Houlston 2001).  These include Familial Adenomatous Polyposis (FAP), due to germline mutations in the tumour suppressor gene APC, and Hereditary Non-Polyposis Colorectal cancer (HNPCC), due to germline mutations DNA mismatch repair enzymes MLH1, MSH2, PMS2 and MSH6. HNPCC accounts for 1-4% of colorectal cancer and is characterised by cancers with DNA microsatellite instability (MSI).  There is good evidence that endoscopic surveillance of patients with high-risk genetic predisposition also prevents cancer (Jarvinen et al. 2000; Dove-Edwin et al. 2005; Dove-Edwin et al. 2006).

Proportion of colorectal cancer due to environmental factors is about 65%, with 5-10% caused by cancer syndromes and the remainder due to low penetrance heritability

Environmental factors such as physical activity, obesity, diet and other exogenous factors also contribute to the aetiology of colorectal cancer (Linseisen et al. 2002; Bingham et al. 2003; Ferrari et al. 2007).    Diet and lifestyle has been found to modify risk across the cancer spectrum e.g., smoking and lung cancer (Doll and Hill 1950).  However, there are difficulties studying the effects of ‘five pieces of fruit a day’ in population studies due to analytical challenges with accurate food monitoring, variation in the fruit types and other confounding variables such as smoking, BMI, etc, and results of studies of environmental factors often vary widely.  Large international studies such as the European Prospective Investigation into Cancer and Nutrition (EPIC) are attempting to unravel the evidence of sometimes contradictory epidemiological studies (Gonzalez 2006).  Genetic predisposition alleles with a low penetrance may be more susceptible to environmental influences which modify an individual’s risk of colorectal neoplasia. There have been very few studies that clearly address the mechanisms of mutational induction by the environment in colorectal cancer.  Although the contribution of individual environmental factors is uncertain, they play an important role in the multifactorial aetiology of colorectal cancer.

 

The normal large bowel

 

The large bowel is embryologically derived from midgut and hindgut which in have their junction at the splenic flexure.  The vascular supply and lymphatic drainage of the large bowel is similarly divided, and this junction is sometimes taken to separate the ‘right’ and ‘left’ colorectum.  In adults, the large bowel lumen is continuous with nine anatomical regions: The caecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, sigmoid colon and the rectum.  The mucosa lies over a basement membrane, underneath is the muscularis mucosa, lamina propria and muscularis propria (Figure 1‑1).

 

 

 

The Wnt signalling pathway and colonic crypt homeostasis

 

The Wnt, and to a lesser extent the TGF-ß, BMP, Notch, and Par polarity pathways are the major players in homeostatic control of the adult epithelium (Sancho et al. 2004).  The surface of the colon is covered by an epithelium composed of four differentiated cell types (enterocytes, enteroendocrine,goblet and Paneth cells) that invaginates at regular intervalsto form crypts.  The bottom of the crypts is occupied by a few stem cells that give rise to actively dividing precursorcells that populate the bottom two-thirds of the crypts. The epithelial cell precursors migrate upward in an ordered fashion, which isalso controlled by Wnt factors, and they stop proliferating when they reach the top third of the crypt, possibly because they are too far from the Wnt source. Meanwhile, they continue their migration and colonise the surface of the colon.After about a week, epithelial cells undergo apoptosis and areshed in the lumen of the gut.  The Paneth cells constitute anexception, as they migrate downward and occupy the very bottomof the crypt (van Es et al. 2005).

Thus, the epithelium of the colon is under perpetual renewal.  Wnt growth factors activate a cascade of intracellular events, which is known as the canonical Wnt pathway that ultimately leads to the expression of a genetic program controlling the co-ordinated expansion, fate and sorting of the epithelial cell population (Figure 1‑2).

The Wnt signalling pathway (McDonald SAC et al. (2006) Mechanisms of Disease: from stem cells to colorectal cancer)

The canonical Wnt signalling cascade controls cell behaviour by activating the transcriptional properties of DNA-binding proteins of the T-cell factor(TCF)/lymphoid enhancer factor-1 family (Clevers 2006). Wnt induces stabilisation of cytosolic ß-catenin, which is transported to the nucleus and associates with TCFs, leading to the expression of specific target genes (McDonald et al. 2006). In the absence of Wnt signalling, ß-catenin is targeted for degradation in proteosomes, and TCFs block expression of Wnt target genes.  Thus activation of the pathway may be demonstrated by nuclear localisation of ß-catenin.  In colorectal cancer mutations in components of the Wnt pathway mimic the effect of a permanent Wnt stimulation, causing epithelial cells to proliferate inappropriately.

Wnt factors can also trigger the activation of at least twoother, ß-catenin-independent, non-canonical pathways. They are referredto as non-canonical signalling and their implication in colorectal cancer, if any, is not yet elucidated.  The list of genes targeted by the Wnt pathway is very long (http://www.stanford.edu/%7ernusse/pathways/targets.html), indicating its wide range of roles in cellular homeostasis.

The transforming growth factor-ß pathway

The transforming growth factor-ß (TGF-ß) superfamily comprises a large number of structurally related polypeptide growth factors and each of these is capable of regulating a complex array of cellular processes (Hata et al. 1998).  In normal epithelial cells including intestinal epithelium, TGF-ß has a major inhibitory role and a substantial body of evidence suggests a role as tumour suppressor.  Neoplastic transformation results in loss of normal growth inhibitory responses to TGF-ß (Kurokowa et al. 1987).  Inhibition of intestinal cell proliferation by TGF-ß treatment results in cell cycle arrest from mid-to-late G1 (Ko et al. 1998).   To date, some of the most important contributors to the growth response seen on TGF-ß exposure appear to involve cell cycle regulatory genes, including C-MYC, CDC25A, and the cyclin-dependent kinase inhibitors (CDKIs) p15INK4B, p21WAF1/CIP1, and p27KIP1 (Ko et al. 1994; Ko et al. 1995).  Other targets of this pathway include the SMAD (Small mothers against decapentaplegic) and BMP genes (bone morphogenetic proteins), important mediators of signal transduction.  In vivo, there is increased expression of both TGF-ß1 and the TGF-ß type II receptor in intestinal epithelial cells as they migrate from the proliferative compartment toward the lumen in both the small intestine and the colon (Winesett et al. 1996).  This pattern of expression is inversely correlated with the mitotic activity in the gut epithelium.  Reduced expression of the TGF-ß type I receptor was been strongly linked to colorectal cancer predisposition (Valle et al. 2008).  However a larger study published subsequently did not demonstrate allele-specific expression or an association polymorphisms within this gene with colorectal neoplasia (Carvajal-Carmona et al 2010).

Colorectal Cancer Development

Pathway from normal colorectal epithelium to cancer

 

Colorectal cancer develops via an adenoma to carcinoma sequence with the accumulation of a number of genetic and epigenetic mutations (Figure 1‑3) (Morson 1968; Fearon and Vogelstein 1990).  The mutations accumulated vary in hereditary cancer depending on the initiating mutation.  In their normal state, tumour suppressor genes inhibit cell proliferation.  Growth inhibition is lost when both alleles are inactivated by mutation and/or epigenetic changes, such as promoter methylation which stifles expression of the gene.  Tumour suppressor genes broadly conform to Knudson’s classic two-hit hypothesis, where inactivation of both alleles is required for tumour suppressor genes to lose their normal function (Knudson 1971).  In contrast, proto-oncogenes act by promoting cell proliferation.  Mutation of these genes leads to abnormal oncogenic over-expression or increased activity of the protein.

The adenoma-to-carcinoma sequence for colorectal cancer is probably most commonly initiated by bi-allelic mutation of the APC tumour suppressor gene.  APC mutations have been found in microadenomas (Otori et al. 1998), the earliest lesion on the pathway (also called aberrant crypt foci (Roncucci et al. 1991)), and in ~60-80% of early sporadic adenomas and carcinomas (Cottrell et al. 1992; Miyoshi et al. 1992; Nakamura et al. 1992).  APC is a key member of the canonical Wnt signalling pathway, and the key mechanism by which mutation of this gene contributes to carcinogenesis is by activation of this pathway.  However, further accumulated mutations in additional genes are required for progression of the early lesions to cancer.

The adenoma-to-carcinoma sequence: A: Aberrant crypt foci are seen using chromoendoscopy with x200 magnification (centre and 2 o’clock) surrounded by normal crypts. An early initiating mutation occurs here, usually a tumour suppressor gene such as APC. B: Adenomatous Polyp: Mutations in proto-oncogenes such as KRAS and BRAF lead to adenomatous polyp formation. C: Other genetic and epigenetic alterations such as promoter hypo-/hyper-methylation cause progression. There are hyperchromatic nuclei with prominent nucleoli indicate highly dysplastic crypts on the left side of this image. D; Adenocarcinoma, with invasion through the muscularis layer, and mucin producing glands with abnormal polarity. This is often associated with genomic copy number variation of regions such as 18q and 17p (P53).

Activating mutations of the oncogenes KRAS (Kirsten rat sarcoma viral oncogene homolog) and BRAF (v-raf murine sarcoma viral oncogene homolog B1), both members of the MAPK (mitogen activated protein kinase) signalling pathway, are found in the transition from early to an intermediate lesion in approximately 50% and 10% of cases respectively (Bos et al. 1987; Rajagopalan et al. 2002; Yuen et al. 2002).  Mutations of codons 12 and 13 in exon 2 of KRAS tend to occur in 30-60% of colorectal carcinomas (Kressner et al. 1998). The KRAS gene product,a 21 kDa protein located at the inner plasma membrane, is involved in the transduction of mitogenic signals.  The Ras protein is activated transiently as a response to extracellular signals such as growth factors, cytokines and hormones that stimulate cell surface receptors (Campbell et al. 1998), and mutations in KRAS constitutively activate the Ras protein.

BRAF V600E substitution mutation

The substitution mutation of BRAF V600E is present in 4-12% of unselected colorectal tumours, and it is associated with sporadic MSI tumours but not HNPCC tumours (Vandrovcova et al. 2006).  MSI tumours outside the context of HNPCC are usually caused by methylation of the MLH1 promoter.  Indeed, there is a hypothesis that some tumours might develop through a separate hyperplastic polyp-serrated adenoma pathway (Spring et al. 2006).

Epigenetic changes such as promoter hypo-/hyper-methylation can cause disregulation of expression of many genes important in colorectal cancer (Hitchins et al. 2005; Hitchins et al. 2006).  Further progression to late type adenoma is associated with loss of 18q in 50% of large adenomas and 75% of carcinomas (Vogelstein et al. 1988; Fearon et al. 1990).  This causes loss of SMAD2 and SMAD4, members of the TGF-ß signalling pathway.  Point mutations of these genes have also been identified in colorectal cancer (Eppert et al. 1996; Hahn et al. 1996; Thiagalingam et al. 1996).  The adenoma to carcinoma transition appears to be associated with loss of 17p (Fearon et al. 1987; Rodrigues et al. 1990; Akiyama et al. 1998).  The 17p locus contains the P53 gene (Baker et al. 1990), the so-called gatekeeper of the cell which has important roles in the regulation of the cell cycle and apoptosis.  Loss of heterozygosity of 17p correlates with missense and truncating mutations in P53 (Baker et al. 1989; Baker, Preisinger et al. 1990).  Tumour invasion and metastasis are associated with loss of 8p (Hughes et al. 2006), and loss of E-cadherin function, a component of adherens-junctions (Hao et al. 1997; Christofori and Semb 1999).

The progression from adenoma to invasive carcinoma probably takes 10-40 years (Ilyas et al. 1999).  However, not all lesions will undergo malignant transformation, the reason for which is unclear.  It may be that the necessary mutations do not accumulate because of death, or because of environmental influences such as diet.

Genetic instability and colorectal cancer

 

Colorectal cancer may be subdivided genetically by the types of mutations which accumulate genome-wide during carcinogenesis.  It had been observed nearly a century ago that most cancers were aneuploid, and it has been noted that the degree of aneuploidy in colorectal cancer correlates with the severity of the neoplastic behaviour (Heim and Mitelman 1989).  A series of deletions, duplications, and rearrangements occur.  Allelic losses appear to be important in the progression from premalignant to malignant neoplasia in the colorectum.  This process is called chromosomal instability (CIN) and accounts for approximately 75% of colorectal cancers.  Ten to 15% are not CIN but do have smaller mutational events which are caused by loss of DNA mismatch repair (Fishel et al. 1993) and are referred to as MSI tumours.  The CpG island mutator phenotype (CIMP) is associated with methylation of promoter regions, CpG rich regions, which causes silencing of genes.  Tumours are often both MIN and CIMP, as methylation of mismatch repair gene promoters usually occurs in sporadic MSI tumours (Kane et al. 1997).

The role of genomic instability in causing and promoting tumour growth remains controversial (Lengauer et al. 1998; Tomlinson and Bodmer 1999).  Some argue that instabilityis necessary for tumourigenesis (Loeb 1991), while others take the viewthat Darwinian selection is the driving force. It is becoming clear that many cancers harbour multiple mutations, the great majority ofwhich probably have no significant effect on tumour growth.  It may well be that some tumours with an inherited DNA repair defect accumulate more mutations than others.

 

Hereditary Colorectal Cancer Syndromes


Hereditary colorectal cancer syndromes

Germline mutations which predispose to multiple polyps

Familial adenomatous polyposis (FAP)

Multiple polyp patients are a clinically heterogeneous group.  Classical familial adenomatous polyposis (FAP; OMIM 175100) is caused by mutation of the APC gene which activates the Wnt pathway (Bodmer et al. 1987; Groden et al. 1991; Clevers 2006).  This gene is somatically mutated in approximately 70% of sporadic colorectal cancer.

Polyposis (carpeting a rectum after a previous ileocolonic anastamosis)

FAP is characterised by over a hundred colonic adenomas, and a high penetrance of colorectal cancer with an average age of cancer presentation of 39 years.  There are also extra-colonic manifestations including intra-abdominal desmoids, duodenal adenomas and congenital hypertrophy of the retinal pigment epithelium (CHRPE).  In attenuated FAP (AFAP) there is a later age of onset of colorectal cancer with a lower penetrance.  The polyps number 10-100 in affected individuals.  This arbitrary distinction is based on clinical characteristics, merely representing different ends of the same phenotypic spectrum of FAP.  Germline mutations in APC account for up to 15% of patients with 5–100 adenomas and can be partitioned out as AFAP.

English: CHRPE - congenital hypertrophy of the...

English: CHRPE – congenital hypertrophy of the retinal pigment epithelium (Photo credit: Wikipedia)

Somatic mutations in the APC gene

From the perspective of APC mutations, the most important functional domains of the APC gene appear to be the first serine alanine methionine proline (SAMP) (axin binding) repeat at codon 1580(Smits et al. 1999) and the first, second and third 20-amino acid repeats (20AARs) involved in ß-catenin binding and degradation. The great majority of pathogenic APC mutations truncate the protein before the first SAMP repeat and leave a stable, truncated protein that encodes 0-3 20AARs.

The ‘just-right’ model. The figure shows the multiple domains of the APC protein and the correlation between the position of the germline mutation and that of the somatic mutation. (a) Germline mutations between the first and the second 20AAR are associated with LOH. (b) Germline mutations before the first 20AAR are associated with somatic mutations between the second and third 20AAR. (c) Germline mutations after the second 20AAR are associated with somatic mutations before the first 20AAR(Segditsas and Tomlinson 2006).

APC is a classic tumour suppressor gene, requiring two hits for inactivation (Knudson 1971).  In colorectal tumours from FAP patients, the germline wild-type allele either undergoes loss of heterozygosity (LOH) or acquires a protein-truncating mutation.  Most somatic mutations occur in a restricted region of the gene, the mutation cluster region (MCR) (Miyoshi, Nagase et al. 1992). The reason for the MCR and relatively low frequency of LOH at APC was discovered from studies of FAP (Lamlum et al. 1999).  It was found that LOH is strongly associated with germline mutations between the first and second 20AAR (codons 1285-1379). Germline mutations before codon 1280 are associated with somatic mutations between the second and third 20AAR (codons 1400 and 1495); and germline mutations after codon 1400 are associated with somatic mutations before codon 1280 (Lamlum, Ilyas et al. 1999; Albuquerque et al. 2002; Crabtree et al. 2003), Most tumours end up with APC alleles that encode a total of two 20AARs(Figure 1‑4).  Similar associations exist for sporadic colorectal cancers. This association has been proposed to cause an optimal level of Wnt signalling/ß-catenin activation (Lamlum, Ilyas et al. 1999; Albuquerque, Breukel et al. 2002).  Whatever the case, it is clear that selective constraints act on colorectal tumours such that some combinations of APC mutations provide a superior growth advantage for the tumour cell.  This is known as the ‘just right’ hypothesis.

Germline APC mutation and phenotype

There is evidence of a genotype-phenotype relationship with regard to APC mutations.  AFAP is associated with germline mutations in three regions of APC: 5’ (codon 1580); and the alternatively spliced region of exon 9 (Knudsen et al. 2003).  Mutations close to codon 1300 are the most commonly found and are associated with a severe phenotype, typically producing over 2000 polyps and earlier-onset colorectal cancer (Nugent et al. 1994; Debinski et al. 1996).  De novo mutations of APC occur in approximately 20% of FAP.  In a small study de novo mutations of APC were found to be more commonly of paternal origin (Aretz 2004).

Somatic mutations in the Wnt signalling pathway in genes other than APC

Figure 1. Wnt doesn't bind to the receptor. Ax...

Figure 1. Wnt doesn’t bind to the receptor. Axin, GSK and APC form a “destruction complex,” and β-Cat is destroyed. Compare to Figure 2. See the article main text for details. (Photo credit: Wikipedia)

The Wnt signalling pathway is activated in approximately 75% of colorectal cancer, and is one of the key signalling pathways in cancer, regulating cell growth, motility and differentiation.  APC binds to the ß-catenin protein which functions in cell adhesion andas a downstream transcriptional activator in the Wnt signallingpathway (Wong and Pignatelli 2002).  Somatic mutations in ß-CATENIN usually delete the whole of exon 3 or target individual serine or threonine residues encoded by this exon (Ilyas et al. 1997; Morin et al.).  These residues are phosphorylated by the degradation complex that contains APC, and hence their mutation causes ß-catenin to escape from proteosomal degradation.  These mutations are particularlyassociated with HNPCC tumours (but not sporadic MSI tumours) (Johnson et al. 2005).  However, less than 5% of all sporadic colorectal cancer has mutation in ß-CATENIN.  In addition somatic mutations have been reported in AXIN1 (Webster et al. 2000) and AXIN2 (Suraweera et al. 2006), the importance of which is uncertain.

MYH-associated polyposis (MAP)

Damaged DNA is repaired by several mechanisms, one of which involves a family of enzymes involved in base-excision repair (BER). The MYH gene encodes a DNA glycosylaseinvolved in the repair of the oxidative lesion 8-oxoguanine, a by-product of cellular metabolism and oxidative damage of DNA.

(8-oxoG, left), in syn conformation, forming a...

(8-oxoG, left), in syn conformation, forming a with (dATP, right). Created using ACD/ChemSketch 10.0 and . (Photo credit: Wikipedia)

The products of three BER repair genes, OGG1, MTH1 and MYH work together to prevent 8-oxo-G induced mutagenesis.  Mutations in MYH cause an autosomal recessive colorectal cancer and polyposis syndrome MYH-associated polyposis (MAP; OMIM 608456) (Al-Tassan et al. 2002).  Somatic mutations in the APC gene in polyps from individuals affected with MAP are almost invariably G to T transversions (Sieber et al. 2003), and it was by understanding the underlying DNA repair mechanism of this mutation, base-excision repair, that MYHwas identified as a candidate-predisposition

English: Schematic of base excision repair

English: Schematic of base excision repair (Photo credit: Wikipedia)

gene. G to T transversion mutations were also identified in KRAS in codon 12 (Lipton et al. 2003).  The adenoma to carcinoma pathway in MAP does not involve BRAF V600E, SMAD4 or TGFBIIR mutations, or microsatellite instability, and the cancers are near-diploid (Lipton, Halford et al. 2003).  Thus, tumours with germline MYH mutations tend to follow a distinct pathway.

The term MYH-associated polyposis (MAP) may be misleading as up to 20% of biallelic MYH mutation carriers are diagnosed with colorectal cancer without polyposis (Wang et al. 2004).  Biallelic mutations in MYH have been found to account for approximately 10% of polyposis patients, but <1% of all colorectal cancer (Halford et al. 2003; Wang, Baudhuin et al. 2004).  The largest population study to date indicates that approximately 0.2% of all colorectal cancer is caused by biallelic mutations in MYH (Webb et al. 2006).  It was demonstrated in the same study that monoallelic MYH mutations are not associated with an increased risk of colorectal cancer.  The MAP phenotype typically falls in to the AFAP group, with extra-colonic manifestations consisting of duodenal polyps but not intra-abdominal desmoids.  Among Caucasians approximately 80% of mutations in MYH causing MAP are Y165C or G382D (Sieber, Lipton et al. 2003).  The E466X mutation is a common founder mutation among Pakistani populations, and the most common mutation in the St Mark’s Hospital MAP population (unpublished data).  Y90X is a founder mutation in Indian populations (Sieber, Lipton et al. 2003).

Hereditary mixed polyposis syndrome (HMPS)

Hereditary mixed polyposis syndrome (HMPS OMIM 601228) is a mixed colorectal tumour syndrome which has been linked to the CRAC1 locus on 15q13-14 (Thomas et al. 1996; Jaeger et al. 2003).  It is a rare condition found in a few families of Ashkenazi descent, with an autosomal dominant inheritance, mixed juvenile, adenomatous and hyperplastic polyps, as well as colorectal cancer (Whitelaw et al. 1997).  The best screening protocol for polyps in HMPS is not clear as the condtion is rare.  In addition genome-wide association revealed common low-penetrance predisposition alleles at the CRAC1 locus which are linked to sporadic colorectal cancer risk (Jaeger et al. 2008).  The gene which causes HMPS was recently identified as a 40kb duplication upstream of the gene GREM1 at the CRAC1 locus (Jaeger et al 2012) which causes disruption of the BMP pathway, a pathway also disrupted in Juvenile Polyposis Syndrome.

The hyperplastic polyp and serrated adenoma pathway

The first series of mixed hyperplastic-adenomatous polyps were described in 1990 (Longacre and Fenoglio-Preiser 1990), and have been an increasingly recognised phenomenon.   Most hyperplastic polyps have no malignant potential, although some recent studies have indicated that some have malignant potential, especially those with serrated architecture (sessile serrated adenomas – SSAs), large hyperplastic polyps, mixed polyps and polyps on the right side of the colon (Torlakovic et al. 2003).

Intermediate magnification micrograph of a SSA.

Intermediate magnification micrograph of a SSA. There are sawtooth serrations at the bases of the crypts which helps differentiate this from hyperplastic polyps (Photo credit: Wikipedia)

Some evidence suggests that some but not all of these tumours develop along a ‘serrated pathway’ separate from the classical adenoma-carcinoma sequence (Sawyer et al. 2002; Spring, Zhao et al. 2006). This serrated pathway involves one group who accumulate BRAF V600E mutations and another separate pathway which involves KRAS mutations(Carvajal-Carmona et al. 2007).  In addition the tumours often have methylation of the MLH1 promoter with subsequent microsatellite instability and CIMP phenotype(Jass 2005).

An inherited hyperplastic polyposis syndrome (HPS) has also been increasingly recognised (Cohen et al. 1981; Sumner et al. 1981). In HPS, multiple serrated polyps develop in the colorectum, and approximately 50% of cases present with at least one CRC (Ferrandez et al. 2004; Young and Jass 2006).  In the WHO criteria, Burt and Jass defined HPS as at least five HPs proximal to the sigmoid colon, two of which are > 1 cm diameter, or more than 30 HPs at any site in the large bowel (Burt 2000). Rashid et al, however, used a different classification system, in which HPS was defined as any person with more than 20 HPs, and separate classes were used for patients with large (>1 cm diameter) or multiple (5-10) HPs (Rashid et al. 2000).  These differing classification systems reflect a syndrome which may be both genetically and phenotypically heterogeneous, but one which is becoming increasingly recognised.

This is a mixed histology polyp from an affected individual in a large hyperplastic polyposis family. It contains both villous, serrated portions, the latter contains a zone of high grade dysplasia with BRAF mutations, the villous section was BRAF wild type.

HPS (sometimes known as the ‘serrated pathway syndrome’ (SPS)) may, in fact, be a heterogeneous group of conditions leading to sporadic and inherited cases of colorectal neoplasia.  There are two alternative clinical criteria for the diagnosis of HPS families (Burt 2000; Rashid, Houlihan et al. 2000).  This syndrome is usually associated with somatic mutations in either BRAF or KRAS, but not both together (Carvajal-Carmona, Howarth et al. 2007), providing further evidence of molecular as well as phenotypic heterogeneity.  BRAF mutations are associated with low-grade microsatellite instability due to methylation in CpG islands (CIMP)(Young, Jenkins et al. 2007).  This may result in loss of expression of DNA repair genes MLH1 and MGMT (O(6)-methylguanine-DNA methyltransferase) in dysplastic mixed polyps from HPS patients, possibly as a result of promoter methylation (Oh et al. 2005).

Linkage analysis in a large family affected with hyperplastic polyposis syndrome deomstrated a maximum LOD score of 2.71 on the short arm of chromosome 8 (8p.21; Monahan et al 2007).

The Galway Family: A large Irish family affected with Hyperplastic Polyposis Syndrome

Other causes of multiple colorectal polyp predisposition

Germline mutations in exon 7 of the AXIN2 gene have recently been very rarely associated with a predisposition to colorectal polyposis and tooth agenesis ((Lammi et al. 2004) OMIM 608615).   Somatic mutations have been found in AXIN2 previously, but germline mutations have not been found in other studies (Lejeune et al. 2006).

Other mutated genes which cause polyps such as SMAD4, PTEN and BMPR1A lead to multiple polyp syndromes with clinically recognisable differences from the above conditions, such as Juvenile Polyposis (OMIM 174900) and Peutz-Jeghers syndrome (OMIM 175200).  The BMPR1A gene product, mutated in Juvenile Polyposis, is a receptor for bone-morphogenetic proteins (BMPs) which are members of TGF-β superfamily and part of the BMP pathway which regulates colonocyte growth and proliferation (Howe et al. 2001).  Germline mutations in PTEN can cause a number of polyposis and multi-systemic syndromes including Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), and the umbrella term ‘PTEN-mutation spectrum’.  We recommend the Cleveland Calculator which can help determine the likelihood of a germline mutation in PTEN for any of these conditions and thus the need for genetic testing;

Cleveland Calculator: http://www.lerner.ccf.org/gmi/ccscore/index.php

Unknown genetic predispositions account for over 50% of all patients who develop 10-100 colorectal adenomas during their lifetime, and for about 20% of those with more than 100 polyps(Lamlum et al. 2000) (Spirio et al. 1993).  To develop as many as 10-100 colorectal adenomas is a priori indicative of an inherited predisposition and many of these patients have a family history of multiple polyps. It is overwhelmingly likely, therefore, that the remaining multiple polyp patients have an inherited disease of an unknown genetic origin. Molecular characterisation of tumours from these patients remains deficient.

Predisposition to colorectal cancer in patients without multiple polyps

Lynch Syndrome/Hereditary non-polyposis colorectal cancer (HNPCC) and related syndromes

Lynch Syndrome (also known as Hereditary non-polyposis colorectal cancer(HNPCC; OMIM 120435)) accounts for approximately 2.2-4% of all colorectal cancer (Hampel et al. 2005).  Lynch Syndrome is a familial cancer syndrome which accounts for approximately 2-3% of all colorectal cancer in the UK.  It has formerly been known as Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), however the phenotype is more complex with multiple extracolonic tumours, for example, so this term has now been largely abandoned.

An Irish family tree with Lynch Syndrome caused by an inherited mutation in MSH2.  Members of this family are affected predominantly with colorectal cancer (CRC), but also small bowel cancer (SBCa), Gastric, Pancreatic, Uterine and other cancers, as well as conditions not linked to Lynch Syndrome such as Crohn’s disease.

LS is an autosomally dominant inherited condition commonly caused by germline mutation in one of four DNA mismatch repair genes, MLH1, MSH2, MSH6 and PMS2.  A minority of these families may be identified because they have multiple affected members diagnosed at an early age.   The Amsterdam Criteria I and II (Vasen et al. 1993; Vasen et al. 1999)(see below) identify patients for colonoscopic and other screening.  Approximately 40-80% of patients meet these criteria, with 50% of the remainder meeting the modified criteria which include extracolonic cancers.  The revised Bethesda criteria (Umar et al. 2004) are used to identify patients for molecular screening of HNPCC, i.e. microsatellite instability ± immunohistochemistry studies.  Approximately 80% of patients are identified using the Bethesda criteria, although the specificity is low.

Immunohistochemistry and microsatellite instability analysis for Lynch Syndrome

Amsterdam I Criteria

  • ≥3 1st degree relatives with colorectal cancer (CRC)
  • ≥2 generations affected
  • One family member below age 50 years of age
  • Exclude familial adenomatous polyposis

Amsterdam II Criteria

  • As for Amsterdam I except that CRC may be substituted by cancer of endometrium, small bowel, or pelviureter.

Most families with LS, however, do not fulfil the Amsterdam criteria. The Revised Bethesda criteria are another set of diagnostic criteria designed to increase the diagnostic yield of testing for LS [7]. For example, all individuals diagnosed under the age of 50 years should be tested for the molecular features of LS in their tumours.  If molecular testing is diagnostic of LS, it can subsequently determine which families should undergo colonoscopic and other investigations, and to screen other high risk family members. The Revised Bethesda guidelines are designed to streamline the clinical diagnostic pathways used to identify mutation carriers in patients with colorectal cancer who might or might not fulfil the Amsterdam criteria, thus increasing diagnostic yield screening for LS.

The identification of such families with Lynch syndrome involves an extensive diagnostic work up comprising of various screening tools combined with genetic and immunohistochemical tests.  Initially the tumour from an affected individual may be tested for features suggestive of this condition by either immunohistochemistry of the mismatch repair proteins and/or DNA microsatellite instability (a hallmark of faulty DNA mismatch repair).  If either of these tests are abnormal, then germline testing may be performed to identify a putative heritable mutation in one of the causative genes.

Patient selection using Amsterdam and revised Bethesda criteria have been applied to clinical pathways in the United Kingdom through the use of national guidelines.  Given the implication of family history and known mortality benefit, the early recognition of Lynch syndrome is highly desirable. There have been concerns over the sensitivity, specificity, and predictive value of already existing guidelines. About 22% of affected individuals do not fulfil either Amsterdam or the Revised Bethesda criteria. As Barnetson et al argues, there might be multiple reasons for this such as small family size, unknown or inadequately taken family history, adoption, and patients without available tumour data [9]. A number of alternative screening models have been developed, such as MMRpredict, PREMM 1,2,6, MMRPro, and MsPath whilst searching for a careening tool that is simple, accurate, and clinically useful for predicting the likelihood of Lynch Syndrome.

Bethesda (revised) Criteria (Umar et al 2003)

  • 1 CRC below age 50 yr
  • Multiple CRC or HNPCC-related cancers
  • CRC with MSI-related histology under 60 years of age
  • CRC or HNPCC-related cancer in ≥1 1st degree relative, < 50 years of age
  • CRC or HNPCC-related cancer in at least two 1st or 2nd degree relatives, any age

MSI-type Histology: Using the revised Bethesda Criteria patients aged 50-60 years should have tumour testing

There is a slight preponderance of right-sided tumours (70% proximal to the splenic flexure) in Lynch Syndrome.  It is a highly penetrant condition which also features extracolonic cancers such as endometrial and gastric cancer.  The adenoma to carcinoma sequence is rapid with interval cancers occurring in 5% of patients despite two-yearly colonoscopic surveillance (Jarvinen, Aarnio et al. 2000).  The tumours are characteristically associated with a local lymphocytic infiltrate and a good prognosis when surgically resected (Jass 2000; Takemoto et al. 2004).

Screening tumours for Lynch Syndrome – is it cost effective?

There are clinical and economic trade-offs when implementing screening protocol on a large scale. As nondirected germline mutation testing for Lynch syndrome is prohibitively expensive at £1000 per gene, MSI and IHC are the screening tests of choice. In view of high costs of testing of all colorectal cancers for MSI or loss or MMR protein, an approach described by Heather Hampel of The Ohio State University, the Revised Bethesda Guidelines were felt to be an appropriate tool to select patients for genetic testing. However, the question remains open: is the “reflex” molecular tumour testing justified clinically and economically? Kastrinos et al, have looked into the popularity of the universal testing across several centres in US. Unsurprisingly, a pessimistic picture emerged showing the low uptake of the concept. The benefits of the universal testing are counterbalanced by practical problems such as an informed consent controversy, practicalities of dealing with the complexity of test results and the resultant implications. The fact that the cost effectiveness of this approach has not been yet validated plays heavily against such approach.

In US, Ramsey et al have carried out a study looking at cost-effectiveness of different strategies for identifying of persons with Lynch syndrome. The average cost per carrier detected using Bethesda guidelines was $15,787, and expanding this strategy to include costs and benefits for first degree relatives greatly improves the cost effectiveness of the program. Expanding the program to first degree relatives leads to savings from intensive screening to exceed the cost of testing.

In Europe, Pinol et al, has carried out a similar study evaluating cost-minimization analysis of identification strategies for MSH2/MLH1-associated Lynch syndrome. Authors concluded that clinical selection of patients using the Revised Bethesda Guidelines followed by either MSI analysis (€11,989 per detected mutation) or IHC (€10,644 per detected mutation) has proved to be more cost effective than performing any of these tests directly (€32,140 and €37,956 per detected mutation, respectively).

Further research has been carried out by Dinh et al in 2010 looking at the cost effectiveness of MMR gene mutations screening, and reached the conclusion that it is comparable to that of already established cancer screening protocols such as colorectal, cervical, and breast cancer screening. Authors argue that primary screening of individuals for MMR gene mutations, starting with the risk assessment between the ages of 25 and 35, followed by genetic testing of those whose risk exceeds 5%, is a strategy that could improve health outcomes in a cost effective manner relative to current practise with the average cost-effectiveness ratio of $26,000 per QALY.

These results echo several European studies, such as that carried out by Pinol V et al, 2005 in Spain, where authors suggest that MSI and IHC testing are equivalent strategies in terms of cost effectiveness when it comes to screening selected patients for MMR mutations

Other non-polyposis predisposition to colorectal neoplasia

About 15% of sporadic colorectal cancers are also microsatellite unstable and feature loss of protein staining on immunohistochemistry but are not caused by germline mutations in mismatch repair genes.  Often they are acquired sporadic type cancers caused by methylation of MLH1.  These associated with a particular genetic pathway which differs from HNPCC by the presence of BRAF V600E mutations, the absence of β-CATENIN exon 3 mutations and a methylator genotype (Young et al. 2005) (Oliveira et al. 2005).  Recently kindreds demonstrating some inheritance of MLH1 promoter methylation have been identified (Suter et al. 2004; Hitchins, Williams et al. 2005), although the evidence for this inherited epimutation is limited to a few case studies and may be related in imprinting (Chong et al. 2007; Hitchins and Ward 2007).

In addition there are a number of families which fulfil Amsterdam criteria but do not demonstrate microsatellite instability (Dove-Edwin, de Jong et al. 2006).  These families are termed by one group familial colorectal cancer type X (Lindor et al. 2005), and have a lower incidence of colorectal cancer occurring at a later age.  The genetic aetiology is not known for these families.

Approximately 93% of colorectal cancer occurs after the age of 50 years, and thus those young patients who develop cancer are likely to have an inherited or other risk factor such as chronic colitis.  The genetic risk is partially made up by inherited mutations which cause HNPCC.  However, there are likely to be a number of other lower penetrance genes which cause cancer predisposition, many of which may have a recessive form of inheritance and few polyps, and therefore a less clearly identifiable phenotype.

Lynch Syndrome


Lynch Syndrome

http://www.youtube.com/watch?v=CnatsiNpjz4

Lynch Syndrome (also known as hereditary non-polyposis colorectal cancer or HNPCC) is a rare condition that may cause a family history of bowel cancer. Conditions that run in families are known as familial or hereditary.

The term non-polyposis differentiates it from another condition called FAP (familial adenomatous polyposis), where hundreds of polyps (small growths) develop in the bowel.

Lynch Syndrome is the most common cause of hereditary bowel cancer. Fewer than 5 in 100 (5%) of all bowel cancers are linked to Lynch Syndrome. Women with Lynch Syndrome also have an increased risk of developing womb (endometrial) cancer.

There is also a slight increase in risk of developing cancer of the ovaries. People with Lynch Syndrome also have an increased risk of stomach, pancreas, biliary and bladder and other cancers.

Knowing about risk and having regular screening may help prevent some cancers and detect others in the early stages when they’re curable.

How is Lynch Syndrome inherited?

Lynch Syndrome is caused by a fault in one of the genes known as the ‘mismatch repair‘ genes. These particular genes normally work to help prevent you getting cancer.

Lynch Syndrome may be suspected in families with close blood relatives who have developed bowel, womb and ovarian cancer over several generations.  We have two copies of each gene – one from each of our parents. If someone has Lynch Syndrome it means they have a healthy gene but also one that’s faulty.

If that person has a child there is a fifty–fifty chance that they will pass on the faulty gene (only one copy of a gene is passed on from each parent).   This called autosomal dominant inheritance.

Lynch Syndrome family with an inherited mutation in the MSH2 gene. Affected members are marked in black

They may have inherited a faulty copy of one of the DNA ‘mismatch’ repair genes.  Four of the mismatch repair genes (known as MLH1, MSH2, MSH6 and PMS2) and one other gene (EPCAM) are responsible for most cases of Lynch Syndrome. So, if a person inherits a faulty copy of one of these genes, it increases their risk of developing bowel cancer and the other types of cancer we’ve already mentioned.

Lynch Syndrome is more likely if there are lots of cases of bowel and womb cancer on one side of the family and if they were diagnosed at an early age. However, not everyone with Lynch Syndrome has a family history of it. This is because some people may be the first in their family to get it.

Lynch Syndrome may be suspected if:

  at least two relatives on the same side of the family have had bowel cancer
  a family member developed bowel cancer at a young age (under 50)
  there are cases of bowel and womb cancer on the same side of the family
  three or more relatives on the same side of the family have had one Lynch Syndrome-type cancer (not necessarily the same kind of cancer).

If you’re worried about cancer in your family, speak to your doctor who can refer you to a family cancer clinic.  You can read more about the science of Lynch Syndrome by clicking here.

Signs and symptoms

Lynch Syndrome itself doesn’t cause any symptoms. It’s an inherited syndrome that means a person has a higher risk of developing bowel and womb cancer.

Sometimes the first sign that a person has Lynch Syndrome is when the symptoms of bowel or womb cancer develop. This generally happens at a younger age than people whose cancers aren’t due to an inherited faulty gene. And there’s usually a history of these cancers in the family.

Symptoms of bowel cancer

Bowel cancer that doesn’t run in families usually develops in people over 50, but in Lynch Syndrome, bowel cancer usually occurs between the ages of 40 and 50 or younger.

Being aware of your normal bowel habit is important, particularly if you have or think you may have Lynch Syndrome.

If you have any of the following symptoms it’s important to get them checked out by a doctor:

  blood on or in the stools (bowel motion)
  diarrhoea or constipation for no obvious reason (ie a change in the normal bowel habit that lasts longer than six weeks)
  unexplained weight loss
  pain in the tummy or back passage
  a feeling of not having emptied the bowel properly after a bowel motion.

Symptoms of cancer of the womb

It’s also important to be aware of the symptoms of womb cancer if you have or think you may have Lynch Syndrome. Any of the following symptoms should be checked out by a doctor:

abnormal vaginal bleeding (between periods, heavier periods or bleeding after the menopause)
pain in the lower abdomen (tummy), back or legs
pain or discomfort during sexual intercourse.

All these symptoms can be caused by conditions other than cancer, but it’s always important to get them checked by your doctor.

How is Lynch Syndrome diagnosed?

It’s possible to find out if someone has Lynch Syndrome by doing a genetic test. This test is first carried out on the family member who has had cancer. If the faulty Lynch Syndrome gene is found in that person, then close family members (not affected by cancer) can be tested (if they wish) to see if they have inherited it.

Testing the Tumour

If a person has a suspected Lynch Syndrome-type cancer, before genetic testing, a special test may be done on a tissue sample taken from the tumour. If this is positive, genetic testing is offered.  It may also guide us in the type of screening you may need over your lifetime.

Initial screening tests of a bowel tumour: Immunohistochemistry and DNA microsatellite instability

Genetic testing

Genetic testing is only carried out if a person is willing to have it. The first step will involve meeting a genetic counsellor to discuss the implications of testing.  Then all that’s needed is a blood sample, but it can take a while (up to a year) to get results as the genes are large and the faulty gene may be difficult to find.

Once the faulty gene has been found, other family members can then be tested for the same faulty gene.

Sometimes the faulty gene can’t be found in the person with the Lynch Syndrome type of cancer (because it’s not Lynch Syndrome or there’s a fault in the gene that research hasn’t yet identified). If no gene change is found other family members can’t be tested. However, based on their family history, they can still have regular bowel tests and womb checks (in women) to reduce their cancer risk.

What the test results mean;

If you have Lynch Syndrome in your family and have the faulty gene you’ll be advised to have regular screening to reduce your risk of Lynch Syndrome-type cancers.
If you have Lynch Syndrome in your family and have not inherited the faulty gene, your cancer risk is the same as anyone else’s. You won’t need screening and your children will not be at increased risk of Lynch Syndrome-type cancers.

Screening to reduce your risk

Knowing your risk of cancer means you can have regular tests (screening). Bowel cancers can be curable when they’re picked up early.

If a person is found to have inherited the faulty gene, they will usually be advised to have regular bowel screening from a young age. This may begin at the age of 25. Some women may also be offered screening for womb cancer.

If the faulty gene wasn’t found in the person with Lynch Syndrome-type cancer, it’s important that you still have screening as you may still be at risk of cancer. This is the same if you decided against genetic testing or couldn’t have it because a family member with Lynch Syndrome-type cancer didn’t want a test.

Bowel screening

Colonoscopies may be performed every 2 years from the age of 25 years in the outpatient endoscopy unit.  This screening is proven to significantly reduce your risk of developing bowel cancer, by as much as 72%.

Some people with Lynch syndrome and a history of stomach (gastric) cancer may also have a regular gastroscopy performed from a later age.

Surgery to prevent cancer

We currently recommend that women consider having a hysterectomy (and removal of ovaries) once they have finished having children as screening of the womb is not effective.

Womb screening

An alternative to surgery involves screening of the womb and ovaries, although this is not proven. You may ask your GP to refer you to our Gynaecology Department for further advice.

The womb can be screened using a procedure called a hysteroscopy or by using a vaginal ultrasound. Your doctor or nurse will explain which test you will have. During a hysteroscopy a thin, flexible tube with a light at the end will be used to look inside the uterus. A vaginal ultrasound scan involves putting a small device that makes sound waves into the vagina. The sound waves are then converted in to a picture by a computer.

Ovarian screening

We don’t know if ovarian screening helps pick up ovarian cancer at an earlier stage. Occasionally some women may be offered it or they may have it done as part of a research trial.

The risk of developing ovarian cancer if you have Lynch Syndrome is much lower than your risk of bowel or womb cancer. Screening can involve a blood test, a vaginal ultrasound or both. The blood test checks the levels of a protein called CA125.

Aspirin and risk reduction in Lynch Syndrome

Recently the results have been published of a trial of the role of aspirin in the prevention of cancer in patients with Lynch Syndrome.  Aspirin taken at 600mg once daily for 2 years from approximately the age of 45 years may reduce the risk of bowel and all other Lynch syndrome associated cancers by over 50%.  Whether this is the right thing for you or not is something you should discuss with your doctor.  Click on this link for more information

Other Treatment

If you develop bowel cancer, it’s likely to be picked up early through having regular colonoscopies. Any Lynch Syndrome-type cancer is treated in the standard way for that type of cancer.

Treatment for bowel cancer will usually involve surgery to remove the cancer. Further treatment with chemotherapy might be needed, depending on the stage of the cancer.

Treatment for womb cancer will usually involve removing the womb (hysterectomy) and the ovaries. Radiotherapy may also be given.

Your feelings

Knowing that you have Lynch Syndrome or are at risk of it can be very difficult to cope with. The uncertainty of not knowing if you will develop cancer isn’t easy to deal with, but it’s important to remember that bowel cancer can be found early and cured. You may have concerns about genetic testing, screening or whether you should have risk-reducing surgery.

It’s important to talk these concerns over with the doctors and nurses caring for you. They’ll be happy to answer any questions you have.

You may have many different emotions, including anxiety and fear. These are all normal reactions and are part of the process that many people go through in trying to come to terms with their condition.

Many people find it helpful to talk things over with their doctor or nurse. Close friends and family members can also offer support.

Further Information

Colorectal Cancer

MacMillan Website Information

Lynch Syndrome International Charity

Email: bowelcancer@wmuh.nhs.uk

 

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CAPP stands for Colorectal Adenoma/carcinoma Prevention Programme


CAPP stands for Colorectal Adenoma/carcinoma Prevention Programme

Insight: International Society for Gastrointestinal Hereditary Tumours (InSiGHT)


 

Insight: International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT)

The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) is an international multidisciplinary, scientific organisation. Its mission is to improve the quality of care of patients and their families with any condition resulting in hereditary gastrointestinal tumours. This mission will be accomplished by:

  1. Encouragement of research into all aspects of gastrointestinal hereditary tumour syndromes.
  2. Education of physicians and other healthcare professionals in the molecular genetics and clinical management of gastrointestinal hereditary tumour syndromes.
  3. Assistance for institutions and individuals interested in beginning or maintaining a registry for families with gastrointestinal hereditary tumour syndromes.
  4. Provision of a forum for the presentation of data, discussion of controversial areas involved in the care of patients and their families, and facilitation of collaborative studies.

 

 

Lynch Syndrome International


 

Lynch Syndrome International – Click Here

The primary mission of Lynch Syndrome International (LSI) is to serve our global communities by focusing on providing support for individuals afflicted with Lynch syndrome, creating public awareness of the syndrome, educating members of the general public and health care professionals and providing support for Lynch syndrome research endeavors.

LSI, an all volunteer organization, is founded and governed by Lynch syndrome survivors, their families, and health care professionals who specialize in Lynch syndrome.

If diagnosed early, we believe Lynch syndrome survivors have favorable outcomes which enhance survival, the longevity and quality of life as well as the emotional well-being of the afflicted.

With the provisions of knowledge, caring and respect for those living with Lynch syndrome, coupled with a common theme of a prevalent positive attitude, we can be change agents, enhancing hope and survivability, impacting the life of countless thousands of people throughout our world.

 

A Family History of Bowel Cancer?


Many people worry about getting bowel cancer, sometimes because a relative has had it. About 1 in 20 people will get bowel cancer in their lifetime.

Bowel cancer is the third most common cancer in the UK for men and the second most common cancer for women. Every year more than 30,000 people will develop it.

The cause of most bowel cancers is not known, but we do know that some risk factors can increase your chances of developing cancer.

Having a particular risk factor for cancer, or being exposed to one, doesn’t mean that you will definitely get cancer – just as not having it doesn’t mean that you won’t. For example if you just have one elderly relative who had bowel cancer, it’s unlikely that you will have a significantly increased risk.

How does family history affect my bowel cancer risk?

Genes carry the biological information we inherit from our parents. They affect the way our bodies grow, work and look.

Changes (mutations) in certain genes can increase the risk of bowel cancer in family members who inherit the genetic change. However, only a small number of bowel cancers are thought to be due to an inherited altered gene (genetic mutation) running in the family.

A genetic mutation that could increase your risk of developing bowel cancer is only likely to be present in your family if you have:

  • One close relative who had bowel cancer at a young age (under 50). Your close relatives are your parents, children, brothers and sisters. They are also sometimes called your first degree relatives.
  • At least two first degree relatives on the same side of the family who developed bowel cancer.
  • Cases of bowel and womb cancer on the same side of your family.
  • Relatives with multiple (over 10) pre-cancerous growths (polyps) in the bowel.

If any of these apply to your family and you’re worried about your risk of developing bowel cancer, you may want to talk to your GP. If your GP thinks there’s a chance you may have an increased risk of developing bowel cancer because of your family history, they can refer you to a family history of bowel cancer clinic at West Middlesex University Hospital or elsewhere.

Inherited conditions which increase the risk of bowel cancer

Up to 30 per cent of people will have a close relative with bowel cancer, however, the degree of risk varies between individuals.  There are some conditions in which inherited genetic changes greatly increase the risk of bowel cancer developing, such as polyposis and Lynch syndrome, where many people in a single family can be affected.  Only about 5 per cent of bowel cancer cases occur in people who have a very strong inherited predisposition.  On the other hand, if only one elderly relative has had bowel cancer, this does not greatly increase your risk.

How can screening reduce my risk of bowel cancer?

The Bowel Cancer Screening Programme (BCSP)

Everyone in England between the ages of 60 and 75 years of age is invited to take part in the National BCSP.  This involves 2 yearly stool tests which are sent through the post, the Faecal Occult Blood Test (FOBT).  People with an abnormal FOBT test will have a colonoscopy.

During a colonoscopy a long, flexible tube is inserted gently into the back passage to look at the inside of the bowel. Bowel screening aims to detect any precancerous changes to the bowel (known as polyps) that could develop into cancer.  These polyps can be removed and cancer prevented.  More information about the BCSP can be found at http://www.cancerscreening.nhs.uk/bowel/.

People with a stronger family history

For most people with a family history of bowel cancer the BCSP is an adequate level of screening.  For some people with a stronger family history we recommend screening with colonoscopy directly rather than the stool tests.  For example this may be from the age of 50 years and every five years for people with 2 close relatives with bowel cancer at a young age.  The type of screening for an individual does vary depending on the degree of risk.  We can discuss this with you in detail in the family history of bowel cancer clinic and work out what suits you best.

Think you have a strong family history of bowel cancer?

Do you know if anyone in your family has had bowel or any other kind of cancer? Talk to your family and make sure you all know your family history.  This would for example be particularly important for those people with a history of bowel cancer diagnosis under age 50 years, or with 2 people in their family affected with bowel cancer.

If you think you have a strong family history of bowel cancer, you should make an appointment with your GP to talk about your concerns. If your GP agrees with you, they can refer you to a specialist family history of bowel cancer clinic at West Middlesex University Hospital. The specialist will go through your family history with you in great detail and ask you to provide accurate information about who has been affected, how old they were when they were diagnosed, and the site where their cancer developed. You may also have to have blood tests as part of this investigation.

You will talk about what types of screening they would recommend, at what age you (and/or other family members) should start being screened and how often you should be screened. Regular screening will ensure that any signs of bowel changes and early cancer are spotted and treated quickly.  You can also discuss other ways to reduce your risk through your lifestyle.

Who we are

Dr Kevin J Monahan (Service lead) spent three years working at Cancer Research UK where I completed my PhD in cancer genetics with funding from the Bobby Moore Fund for Bowel Cancer Research.  I worked in the Family Cancer Clinic at St Mark’s Hospital in Harrow during this time.  I work with Dr Iain Beveridge, Dr Carole Collins, Dr Joel Mawdsley and Dr Krishna Sundaram in the Gastroenterology Department.
Athalie Melville is a Genetic Counsellor from the Kennedy Galton Clinical Genetics Centre in Northwick Park, Harrow.  She sepnd time also within the clinic seeing patients before they have genetic testing.

The other members of the team are from the Departments of Gastroenterology, Endoscopy, Colorectal Surgery and Cancer Services at West Middlesex University Hospital.

Familial Adenomatous Polyposis (FAP)

FAP (familial adenomatous polyposis) is a rare genetic disease that causes a family history of cancer and multiple polyps in the bowel.

Lynch Syndrome

Lynch Syndrome (also known as hereditary non-polyposis colorectal cancer or HNPCC) is a rare condition that may cause a family history of bowel cancer, and causes 1000 cases of bowel cancer in the UK annually. Anybody diagnosed with bowel cancer under 50 years of age should be tested for this condition (unless they have over 10 polyps)

Endoscopic procedures

Sigmoidoscopy patient information sheet

Gastroscopy patient information sheet

Colonoscopy patient information sheet

Information for GPs

Click here to download information sheet for GPs

Contact details

The Family History of Bowel Cancer Clinic,
Gastroenterology Department
West Middlesex University Hospital,
Twickenham Road, Isleworth,
London TW7 6AF.
Email: bowelcancer@wmuh.nhs.uk
Telephone: 020 8321 5351
Fax: 020 8321 5024
 

Useful web pages

Beating Bowel Cancer

Bowel Cancer UK

Cancer Research UK: High risk groups for bowel cancer

Macmillan: Information about bowel cancer

West Middlesex University Hospital – Department of Gastroenterology

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