Peutz–Jeghers syndrome

This tag is associated with 5 posts

Juvenile Polyposis Syndrome

Juvenile polyposis (JPS) is defined by the presence of multiple hamartomatous polyps of the colon and rectum.  Estimates of the population prevalence of Juvenile Polyposis syndrome suggest a frequency of around 1:100 000.  It accounts for less than 0.1% of all colorectal cancer cases.

Histological differences and topographical distribution within the gastrointestinal tract serve to distinguish between this disorder and Peutz-Jeghers syndrome (PJS). Juvenile hamartomatous polyps have an apparently normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria with smooth muscle fibres, which distinguishes these from PJS polyps. The glandular proliferative characteristics of adenomas are typically absent.

English: Very low magnification micrograph of ...

English: Very low magnification micrograph of a gastric juvenile polyp. H&E stain. Features of juvenile polyps: Dilated glands. Increased lamina propria & inflammation. Eroded surface. Stalk. Related images Image:Gastric juvenile polyp – 2 – very low mag.jpg (Photo credit: Wikipedia)

The term ‘juvenile’ refers to the polyp type rather than to the age of onset, although most individuals with juvenile polyposis have some polyps by 20 years of age. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than a hundred. Juvenile polyposis usually manifests during childhood, but diagnosis of the condition is confounded by the occurrence of isolated juvenile-type polyps in children. These solitary polyps are noteworthy because their identification in childhood does not necessarily indicate a heritable cancer predisposition syndrome, and they do not appear to be associated with excess cancer risk.  In contrast, juvenile polyposis is associated with a colorectal cancer risk of around 10-38% and a gastric cancer risk of 21%.

If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk of GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have been reported.

Molecular Genetics

Around 20% of cases are due to mutations in the SMAD4 gene, while a further 20% are due to mutations in another gene in the same TGF-beta molecular signaling pathway, BMPR1A, indicative of genetic heterogeneity.  Mutations in BMPR1A have been particularly implicated in European populations and SMAD4 mutations may have a more aggressive clinical phenotype.  A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) may be present in 15%-22% of individuals with an SMAD4 mutation.

Clinical Diagnosis

JPS is clinically diagnosed if any one of the three following findings is present:

  • More than five juvenile polyps of the colorectum
  • Multiple juvenile polyps throughout the GI tract
  • Any number of juvenile polyps and a family history of juvenile polyps

Testing relatives at risk: When the family-specific mutation is known, it is appropriate to perform molecular genetic testing on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance and intervention.

UK BSG Screening Guidelines

Colorectal surveillance

< Large bowel surveillance for at-risk individuals and mutation carriers every 1-2 years is recommended from age 15-18 years, or even earlier if the patient has presented with symptoms. Screening intervals could be extended at age 35 years in at-risk individuals. However, documented gene carriers or affected cases should be kept under surveillance until age 70 years and prophylactic surgery discussed. The intervention should visualise the whole colon and so colonoscopy is the preferred modality.  Although isolated juvenile polyps are relatively common, juvenile polyposis is rare and consequently experience is limited.  There are few large descriptive studies, and no comparative study to demonstrate potential benefit. Nonetheless, there is a substantial risk of colorectal cancer amounting to 10-38%.  Many polyps are located in the right colon, and so the whole colon should be visualised. There is particular risk of malignancy in cases where there is adenomatous change, or where there is a dysplastic element to the polyps.

Upper gastrointestinal surveillance

< Upper gastrointestinal surveillance every 1-2 years is recommended from age 25 years, contemporaneously with lower gastrointestinal surveillance.  The risk of gastric and duodenal cancer in juvenile polyposis is round 15-21%.


Peutz-Jeghers Syndrome (PJS)

English: Structure of the LKB1 (pink)- STRAD (...

Structure of the LKB1 protein

Disease characteristics. Peutz-Jeghers syndrome(PJS (OMIM 175200)) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation.  Gastrointestinal cancer risks include gastro-oesophageal, small bowel, pancreatic and colorectal cancers with a cumulative risk of 57% by the age of 70.  here is a 50% lifetime risk of breast cancer, and clinicians managing PJS patients should ensure breast screening arrangements are in place. In 2063% of cases, inactivating mutations can be identified in the gene STK11 (LKB1). There is evidence for genetic heterogeneity with a possible further locus on chromosome 19q. Estimates of the population prevalence of PeutzJeghers syndrome suggest a frequency of around 1:50 000.

Peutz-Jeghers-type hamartomatous polyps are most common in the small intestine (in order of prevalence: in the jejunum, ileum, and duodenum) but can also occur in the stomach, large bowel, and nasal passages. Gastrointestinal polyps can result in chronic bleeding and anemia and cause recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection.

English: Low magnification micrograph of a Peu...

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

Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa. Hyperpigmented macules on the fingers are common. The macules may fade in puberty and adulthood. Individuals with Peutz-Jeghers syndrome are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers). Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer. Males occasionally develop calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia.

Diagnosis/testing. The diagnosis of Peutz-Jeghers syndrome is based on clinical findings. In individuals with a clinical diagnosis of PJS, molecular genetic testing of STK11 (LKB1) reveals disease-causing mutations in nearly all individuals who have a positive family history and approximately 90% of individuals who have no family history of PJS. Such testing is available clinically.


English: A graphical representation of the nat...

English: A graphical representation of the natural history of Peutz-Jeghers syndrome. Most patients will develop melanotic macules during the first year of life and a patient’s first intussusception usually occurs between the ages of six and 18 years old. Cumulative lifetime cancer risk begins to rise in middle age. Cumulative risks by age 70 for all cancers, gastrointestinal (GI) cancers, and pancreatic cancer are 85%, 57%, and 11%, respectively. (Photo credit: Wikipedia)

Colorectal surveillance

Large bowel surveillance is recommended 2-yearly from age 25 years. The intervention should visualise the whole colon and so colonoscopy is the preferred mode of surveillance. PJS is rare and so evidence on effectiveness of surveillance is limited to case series and anecdote.  The risk of colorectal cancer increases with age being 3%, 5%, 15%, and 39% at ages 40, 50, 60, and 70 years, respectively. Males may be at greater risk. There is also an excess risk of small bowel, pancreatic and oesophago-gastric cancer. The risk for all gastrointestinal cancers combined is 1%, 9%, 15%, 33%, and 57% up to ages 30, 40, 50, 60 and 70 years, respectively.154

Treatment of other manifestations:

Upper gastrointestinal surveillance is recommended 2-yearly from age 25 years, comprising gastro-duodenoscopy. Intermittent MRI enteroclysis or small bowel contrast radiography is recommended.

There is an elevated risk of gastric malignancy in PeutzJeghers syndrome amounting to around 510%.  Although evidence from pooled case series indicates that small intestinal cancer is rare, the risk is sufficient to merit intermittent imaging.  MRI enteroclysis appears appropriate for surveillance because it avoids repeated radiation exposure in young individuals and has very good sensitivity and overall accuracy for small bowel polyps in PJS as well as for patients with small bowel tumours who do not have PJS.  However, video capsule endoscopy is also an option, with evidence of better sensitivity than MRI enteroclysis for smaller lesions in small bowel polyposis syndromes in one small comparative study.

Testing of relatives at risk: If the family mutation is known, offer molecular genetic testing to at-risk relatives so that morbidity and mortality can be reduced in those with the family-specific mutation by early diagnosis and treatment and appropriate surveillance; if the family mutation is not known, offer clinical diagnostic evaluations to identify those family members who will benefit from early treatment and appropriate surveillance.

Other: Although not studied in individuals with PJS, the following could be considered: prophylactic mastectomy to manage high risk for breast cancer and prophylactic hysterectomy and bilateral salpingo-oophorectomy after age 35 years or after child-bearing has been completed to prevent gynecologic malignancy.

Genetic counseling. Peutz-Jeghers syndrome is inherited in an autosomal dominant manner. About 50% of affected individuals have an affected parent and about 50% have no family history of PJS; the proportion of cases caused by de novo gene mutations is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. The risk to the offspring of an individual with a pathogenic STK11 mutation is 50%. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known

The Family History of Bowel Cancer Registry

What is your family history?

What is your family history?

The Family History of Bowel Cancer Registry was founded in 2010. It has been a useful resource for hereditary and non-hereditary colorectal cancer research conducted at West Middlesex University Hospital. Our clinicians and researchers have utilised the information our registry provides for research on the causes of colorectal cancer. It helps to link our patients with their screening and surveillance programmes, and also in to local and national research projects such as the Cancer Research UK study CORGI (COloRectal Gene Identification Study). The registry also provides services to families, community health professionals, and the general public, including educational materials and programs on hereditary colorectal cancer syndromes, cancer genetics, and current research.

Family History of Bowel Cancer Registry;

  • Evaluation of family histories based on questionnaires and medical records
  • Genetic counseling
  • Recommendations regarding cancer management
  • Development and implementation of research studies
  • Provide information for patients and professionals about cancer genetics research
  • Referral of patients and service providers to community and hospital resources
  • Development of literature for use by public and private agencies and individual patients and their families

Conditions and Syndromes;

  • Family History of Cancer
  • Lynch Syndrome
  • Familial colorectal cancer syndrome-X
  • Familial adenomatous polyposis coli (FAP)
  • MUTYH-associated polyposis (MAP)
  • Peutz-Jeghers syndrome (PJS)
  • Juvenile polyposis
  • Hyperplastic polyposis syndrome (HPS)
  • Hereditary mixed polyposis syndrome (HMPS)
  • PTEN-mutation spectrum


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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:

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.


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.


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)








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