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FAP

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Squaring Genetic vs Clinical Findings in Familial Polyposis


Journal CoverPrevalence and Phenotypes of APC and MUTYH Mutations in Patients With Multiple Colorectal Adenomas

Grover S, Kastrinos F, Steyerberg EW, et al

JAMA. 2012;308:485-492

Summary

Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene and 2 different, or biallelic mutations, in the MUTYH gene. However, not all patients with colorectal polyposis are found to carry mutations on these genes. In addition, it is unclear how the extent of polyp burden or the age at development of the first adenoma corresponds to the likelihood of finding mutations in either of these 2 genes.

In an effort to better characterize the mutation frequency in patients with multiple colorectal adenomas, this study tested for APC and MUTYH mutations in 8676 individuals over 8 years. Each person’s cancer history, adenoma count, and family history of cancer or colorectal adenomas was reported by clinicians ordering the genetic testing.

The study found that patients with classic polyposis were very likely to carry an APC mutation: 80% of those with ≥ 1000 colorectal adenomas and 56% of those with 100-999 adenomas carried an APC mutation. APC mutations were prevalent even in individuals with fewer than 100 adenomas, with mutations seen in 10% of those with 20-99 adenomas and in 5% of those with 10-19 adenomas.

With regard to MUTYH mutations, the frequency was low in individuals with≥ 1000 adenomas (2%) but was fairly consistent in those with 10 colonic adenomas, those who present with multiple adenomas at an unusually young age, or those who have a family history consistent with FAP. The findings of the current study support testing in these individuals and demonstrate that the greater the number of polyps, the greater the likelihood of identifying a mutation.

However, multiple factors can complicate the value of genetic testing in clinical practice. The clinical phenotype of biallelic MUTYH mutations is quite varied; reports show that some mutation carriers can have hundreds of polyps, whereas others with colon cancer have no reported polyps.[2] Also, overlap among the clinical phenotypes of Lynch syndrome, MUTYH-associated disease, and attenuated FAP or other polyposis conditions may require clinical expertise for appropriate diagnosis and management. Finally, some controversy remains with regard to risk (if any) for colon cancer in persons with only 1 MUTYH mutation, and management in these patients is uncertain.[3]

At the same time, not all individuals manifesting colonic polyposis harbor a mutation in APC or MUTYH, and management is not straightforward in patients with polyposis but no identified mutation. Clearly, there are cases of unknown etiology, and there are probably as-yet unidentified genes that may predispose to adenomatosis. But changing technologies and testing standards can also affect interpretation of genetic test results. For example, polyposis testing was once only pursued in persons with > 20 polyps, whereas guidelines now recommend that testing be done in all patients who have ≥ 10 adenomas,[1] so historically “negative” tests may need to be revisited in the future.

Similarly, individuals tested before the availability of APC deletion/duplication analysis and MUTYH testing must be reassessed. Indeed, in the past few months, new and more efficient molecular testing modalities, so-called next-generation sequencing, have allowed the commercial launch of several cost-efficient gene panels that can test multiple genes at once for polyposis and nonpolyposis mutations. This may prove particularly helpful in evaluating patients with low polyp counts.

Current recommendations note that individuals with multiple adenomas or a family history of colon cancer be referred for genetic counseling. However, a lack of family history does not exclude the possibility of FAP, because an individual can harbor a de novo mutation; genetic testing for a hereditary cancer syndrome can thus be pursued on the basis of age, polyp count, and family history. In the absence of an identified mutation, family history as well as clinical presentation can be used to determine whether the individual may be at increased risk for other syndromes, and an empiric screening and prevention protocol can be established.

via Squaring Genetic vs Clinical Findings in Familial Polyposis.

Familial adenomatous polyposis (FAP)


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Familial adenomatous polyposis (FAP)

Multiple polyp patients are a clinically heterogeneous group. Classical familial adenomatous polyposis (FAP; OMIM 175100) is caused by a germline mutation of the APC gene (at the locus 5q22-21) which activates the Wnt pathway (Bodmer et al. 1987; Groden et al. 1991; Clevers 2006). APC is also somatically mutated in approximately 70% of sporadic colorectal cancer.  However these cases are not caused by inherited mutations in the gene.

Polyposis (carpeting the rectum 20 years following a previous ileorectal 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 classical FAP, the risk of developing colorectal cancer exceeds 90% by age 70 years without prophylactic surgery.  The risk of gastroduodenal cancer is about 7%.  Around 25% of all cases are due to new mutations in the APC gene and so there is no previous family history. Nonetheless, children of individuals with a new mutation are at 50% risk of inheriting the condition.

The population prevalence of FAP is estimated at 1:14 000.  Owing to highly effective surgical prophylaxis, FAP accounts for only 0.07% of incident colorectal cancers in modern practice.  As registries and genetic services improve detection of at-risk family members, the proportion of colorectal cancer cases due to FAP should reduce, limited only by the proportion due to new mutations, which account for 25% of cases.

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 categorised AFAP.

English: CHRPE - congenital hypertrophy of the...

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

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

Somatic mutations in the APC gene

With regard to 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 a genotype-phenotype relationship determined by the precise location of the APC mutation. 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)

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 particularly associated 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.
Screening and Managment of FAP

Establishment of FAP registries

Families with FAP should be referred to the regional clinical genetics service or other specialist service that can facilitate risk assessment, genetic testing and screening of family members. Some regional services have specific FAP registers that facilitate regular follow-up. FAP registries have been shown to improve outcomes by systematic and structured delivery of management, monitoring interventions and surveillance, as well as serving as a focus for audit.

Large bowel surveillance for FAP family members Annual flexible sigmoidoscopy and alternating colonoscopy should be offered to mutation carriers from diagnosis until polyp load indicates a need for surgery.198 In a small minority of families where no mutation can be identified and genetic linkage analysis is not possible, family members at 50% risk should have annual surveillance from age 13e15 until age 30 years, and every 35 years thereafter until age 60. Surveillance might also be offered as a temporary measure for people with documented APC gene mutations and a significant polyp load but who wish to defer prophylactic surgery for personal reasons. Such individuals should be offered 6-monthly flexible sigmoidoscopy and annual colonoscopy. As in Lynch syndrome, chromoendoscopy or narrow band endoscopy may have a place in surveillance for attenuated FAP, but the utility of these techniques merits further appraisal and must not replace conventional endoscopic approaches. Surgery can be deferred if careful follow-up is instigated and the patient is fully aware of the risks of cancer. This is especially the case for attenuated FAP but can also be useful in the management of classical FAP for individuals who have a low polyp burden in terms of size, multiplicity and degree of dysplasia. The cancer risk increases substantially after 25 years, and so surgery should be undertaken before then unless polyps are sparse and there is no high-grade dysplasia. If colectomy and ileorectal anastomosis are performed, the rectum must be kept under review annually for life because the risk of cancer in the retained rectum is 1229%.The anorectal cuff after restorative proctocolectomy should also be kept under annual review for life.

Prophylactic colorectal surgery

Patients with typical FAP should be advised to undergo prophylactic surgery between the ages of 16 and 25 years, but the exact timing of surgery should be guided by polyp numbers, size and dysplasia and fully informed patient choice influenced by educational and child-bearing issues. Surgical options include proctocolectomy and ileoanal pouch or a colectomy with ileorectal anastomosis.

People with proven FAP require prophylactic surgery to remove the majority of at-risk large bowel epithelium. Colectomy and ileorectal anastomosis is associated with a 1229% risk of cancer in the retained rectum, whereas restorative proctocolectomy is associated with a very low risk of cancer in the pouch or in the retained mucosa at anorectum. Ileoanal pouch construction may be associated with impaired fertility.  It is clear that case identification and prophylactic surgery have markedly improved survival in FAP.

Upper gastrointestinal surveillance in FAP

Because of the substantial risk of upper gastrointestinal malignancy in FAP, surveillance of this tract is recommended. While gastroduodenal polyposis is well recognised in FAP and surveillance practice is established practice in the overall management, there is limited evidence on which to gauge the potential benefit of surveillance. However, the approach seems reasonable, and 3-yearly upper gastrointestinal endoscopy is recommended from age 30 years with the aim of detecting early curable cancers. Patients with large numbers of duodenal polyps should undergo annual surveillance.

Gastroduodenal and periampullary malignancies account for a small, but appreciable, number of deaths in patients with FAP. Duodenal polyposis occurs in approximately 90% of FAP patients and the overall lifetime risk of periampullary cancer is 35%.Advancing age and mutation location within the APC gene appear to have an effect on duodenal carcinoma risk.  Almost all FAP patients have some abnormality on inspection and biopsy of the duodenum by age 40.  The degree of duodenal polyposis can be assessed using an endoscopic/histological scoring system (Spigelman classification143), which can be helpful in predicting the risk of duodenal cancer. The worst stage (IV) has a 10-year risk of 36% and stage 0 negligible risk.207 Hence, it seems reasonable to offer 3-yearly upper gastrointestinal surveillance from age 30 years and more frequently if there is extensive polyposis. However, it should be noted that the effectiveness of this intervention in reducing mortality is unknown, especially since duodenal polypectomy is unsatisfactory208 and prophylactic duodenectomy is a major undertaking with substantial attendant morbidity and mortality.

 

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.

Polyposis


Familial Adenomatous Polyposis (FAP)

FAP (familial adenomatous polyposis) is a rare disease that causes a family history of bowel cancer.  FAP is usually inherited from a parent who has the condition, and is caused by a mutation on the APC gene on chromosome number 5.  Each child, boy or girl, born to a person with FAP has a 50:50 chance of inheriting the gene that causes it. This is the same as the chance of getting a head or a tail when you toss a coin. This is known as an ‘autosomal dominant’ inheritance.  If a person has not inherited the gene that causes FAP then that person’s children will not be at any increased risk of getting polyposis.  This is a family tree for one of our polyposis families with an inherited mutation in APC

You can have FAP even if there are no other cases in your family. In about 1 in 4 cases, the gene mutation comes about by accident and not because you’ve inherited it.

FAP is responsible for about 1 out of every 100 bowel cancers (1%). FAP causes lots of small non cancerous growths (benign polyps) to develop in the large bowel (colon). But some of these can develop into cancer over a long period of time. Because people with FAP have so many polyps, they have a high risk of getting bowel cancer. By their 40’s or 50’s, it is almost certain they will have bowel cancer. Specialists recommend that people with FAP have surgery to have all of their colon removed by the age of 25 to prevent them getting bowel cancer.

FAP is characterised by the presence of hundreds or thousands of adenomatous polyps in the colons of affected individuals, which  often start in adolescence. Cancerous polyps are very common in this condition, usually by age 40, without active management of the polyps and screening on a regular basis. Diagnosis is usually made following colonoscopy to confirm the presence of polyposis. Testing for mutation of the APC gene currently detects 95% of mutations present.

Screening

In families where there is a clear history of FAP, screening usually commences by the age of 13 with annual sigmoidoscopy for the first few years, and then annual colonoscopy using a special dye spray. Where FAP is suspected, your GP will refer you to the local Regional Genetics Centre (such as the family history of bowel cancer clinic at West Middlesex University Hospital) for support and on-going management of the condition, because it has been known to affect adolescents and teenagers.  Screening for the other complications of FAP is also possible, and the local Regional Genetics Centre will be able to advise about these on an individual basis, once they have seen you and your family in their clinic.

The treatment for FAP is usually a planned operation to remove the affected part of the colon once polyposis has become established. This normally occurs in the late teens or early twenties.   Later in life you may require other screening such as a gastroscopy which will be discussed with you in detail.  These are very rare conditions and you will need the specialist help and support of an experienced colorectal team to help make the right decisions for the individual affected.

Other Polyposis syndromes

 MUTYH-Associated Polyposis (MAP)

This is another inherited syndrome which may cause multiple polyps and cancer of the large bowel, similar in many respects to FAP.  However there is often not a family history because the risk must be inherited from both parents who are usually unaffected themselves.  It is caused by a mutation on the MUTYH gene on chromosome number 1.  This is called autosomal recessive inheritance, and as demonstrated in the family tree below in which 2 brothers were diagnosed with polyposis and colorectal cancer in their 30s, means that only a single generation is likely to be affected.  We can offer genetic testing for this condition however.  People affected with this condition have a lower risk of developing cancer in their lifetime compared to FAP.

MYH-Associated Polyposis Family with Recessive Inheritance

 Peutz-Jeghers Syndrome

This is a rare condition where a type of polyp called ‘hamartomatous’ can arise anywhere in the small or large bowel, and these polyps can develop in to cancer.  There is often a characteristic feature present from childhood called buccal pigmentation which means that there is freckling on the lips and mouth.  This kind of freckling can develop in adults but this is not usually due to Peutz-Jeghers Syndrome but perhaps another benign condition called Laugier-Hunziker syndrome, which is no concern.  There are other hamartomatous polyposis syndromes such as PTEN hamartoma tumor syndrome which includes Bannayan-Riley-Ruvalcaba Syndrome.

English: Low magnification micrograph of a Peu...

English: Low magnification micrograph of a Peutz-Jeghers type intestinal polyp. H&E stain. (Photo credit: Wikipedia)

Hyperplastic Polyposis Syndrome (HPS) 

In HPS (also known as serrated polyposis syndrome) there may be just a few large hyperplastic polyps, mixed adenomas or sessile serrated adenomas, sometimes called serrated adenomas, usually on the right hand side of the large bowel.  They have a significant cancer risk and should be removed.  They are sometimes associated with a history of cancer in the family.  It may be associated with cigarette smoking.

Sessile serrated adenoma2

Sessile serrated adenoma2 (Photo credit: Wikipedia)

 

 

 

 

 

 

 

Further Information
Read the ‘related articles’ on this blog below or try out these links to other sites

http://www.polyposisregistry.org.uk/FAPintro/FAPhome.htm

http://www.patient.co.uk/doctor/Peutz-Jeghers’-Syndrome.htm

Email: bowelcancer@wmuh.nhs.uk

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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Polyposis Registry


 

Polyposis Registry – Click Here

The world’s original polyposis registry is based at St Mark’s Hospital, Harrow.  FAP (Familial Adenomatous Polyposis) is an inherited condition which mainly affects the large intestine (also known as the large bowel or colon and rectum). People with FAP develop many polyps (which are like small cherries on stalks) inside their large bowel. There are many different types of polyps but these particular polyps are called adenomas (the “adenomatous” in FAP). An adenoma can in time turn into a cancer which is why it is so important to make sure anyone at risk of inheriting FAP is examined.

FAP is a serious condition unless detected early when it can be treated.

 

FAP Gene Support Group


 

FAP Gene Support Group – Click here

(Familial Adenomatous Polyposis) FAP is an inherited condition which mainly affects the large intestine (also known as the large bowel or colon and rectum). People with FAP develop many polyps (which are like small cherries on stalks) inside their large bowel. There are many different types of polyps but these particular polyps are called adenomas (the “adenomatous” in FAP). An adenoma can in time turn into a cancer which is why it is so important to make sure anyone at risk of inheriting FAP is examined.

FAP is a serious condition unless detected early when it can be treated.

 

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.

 

 

British Guidelines for Screening High Risk Groups


 

British Guidelines for Screening High Risk Groups – Click this Link to Download

Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002)

 

Family History of Bowel Cancer Clinic – Information for GPs


Information for GPs – click this link for Referral Guidelines Download

Family History of Bowel Cancer
GP Referrals
    External resourcesBritish Society of Gastroenterology(BSG) and the Association of Coloproctology for Great Britain and Ireland(ACPGBI) Guidelines

Bowel Cancer Screening Programme (BCSP) information pack for GPs

NICE Colorectal Guidelines

Family History Questionnaire

Patient Information

MacMillan

Cancer Research UK

 

   
   
   
What to consider in Primary Care before referring

  • Up to 9% of an average population will have at least one first degree relative (FDR i.e. sibling, parent or child) and over 20% a second degree relative (SDR i.e. Grandparent, uncles, aunts, half siblings) with bowel cancer.
  • For most of these there is no proven benefit for increased surveillance above that of the rest of the population i.e. the bowel cancer screening programme (BCSP).
  • However a significant proportion may benefit from outpatient assessment for screening interventions and/or genetic testing.
  • There is no direct access colonoscopy service, patients should be referred for outpatient assessment for the appropriateness of this procedure.
  • Information about the BCSP for GPs including referral guidelines in contained in the link above.  Currently this is still a faecal occult blood (FOB) test based screening test from the age of 60 years only, although in a few years this may become a flexible sigmoidoscopy based screening programme.
 
Approach to assessing patients with a family history of bowel cancer – Full historywith reference to the following points

  • Full family history detailing all family members affected
  • Age of diagnosis of relative (s) with bowel cancer
  • Extracolonic cancer(s): Age of diagnosis and site
  • Specific details of previous genetic testing (with written documentation if possible)
  • Patients other risk factors e.g.
    • Body mass index
    • Physical activity
    • Diet
    • Smoking and alcohol consumption
    • Age
    • Gender
  • Symptoms – often these patients will be asymptomatic, but consideration of any alarm symptoms should be included and referred irrespective of family history according to NICE referral guidelines

Examination should specifically include

  • Palpable masses on external, or digital rectal examination.
  • Superficial lesions including moles, buccal pigmentation, etc.
       
PRIMARY CARE Low risk groups: Although many of these patients may seek reassurance, according to national guidelines they do not require screening above and beyond the rest of the population (i.e. BCSP).

  • 1 FDR over age 50 years at diagnosis.
  • 2 SDRs.
  • Family history of any relative with < 10 polyps found on colonoscopy.

They may be offered lifestyle modification advice in addition to reassurance.  Lifestyle interventions proven to reduce risk of bowel cancer include

  • Regular physical activity
  • Weight loss if obese (to a normal BMI)
  • Diet: High fibre, low red meat, 5 pieces of fruit & veg per day
  • Smoking cessation
  • Moderate or low alcohol consumption (any alcoholic beverage)
     
Referral ThresholdModerate risk groups should be referred for assessment for screening from the age of 50 years onwards and not before in the absence of other indications.

  • 1 FDR under age 50 years at diagnosis.
  • ≥ 2 FDRs any age.
  • 1 FDR and 1 SDR same side of the family any age.

High risk groups should be referred at any age.  They account for approximately 5% of all bowel cancer.

  • 3 FDR with bowel cancer – one diagnosed under age 50 (e.g. Lynch Syndrome or Hereditary non-polyposis colorectal cancer (HNPCC)).
  • A family history with multiple affected members in more than one generation
  • A previously characterised high risk patient or relative (i.e. with a known cancer syndrome such as Familial Adenomatous Polyposis Coli (FAP)) not currently undergoing surveillance.
  • The presence of a germline pathogenic mutation in a colorectal cancer susceptibility gene if previously tested.

There is strong evidence that screening moderate and high risk groups reduces colorectal cancer mortality, with much lower than expected incidence in screened populations compared to expected ONS data

Secondary care resource:Refer to Gastroenterologist if moderate or high risk

  • West Middlesex University Hospital

 

Gastroenterology Department

West Middlesex Hospital

Twickenham Road, Isleworth, TW6 7AF

Phone: 020 8321 5351

Fax:     020 8321 5152

Email: bowelcancer@wmuh.nhs.uk

 

 

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