Colorectal cancer

Introduction: high-risk familial syndromes

From Cancer Guidelines Wiki

Background[edit source]

Approximately 5% of all colorectal cancers and 10–15% of colorectal cancers diagnosed before age 50 years are caused by high-risk germline mutations.[1][2] Genetic knowledge is rapidly expanding and new discoveries are likely to explain cases of heritable predisposition for which a mutation cannot currently be identified. For example, polymerase proofreading-associated polyposis (PPAP) has recently been described and accounts for a small number of families with polyposis.[3] Similarly, mutations in NTHL1 have been found to cause a rare autosomal recessive form of polyposis.[4]

Genetic testing for familial cancer syndromes is under going rapid change as technology improves and costs for more extensive testing strategies drop. Testing strategies are moving towards testing a panel of genes covering all polyposis conditions, or a non-polyposis Lynch panel, or both where the phenotype is unclear. Some centres offer whole exome sequencing but with analysis only of those genes which are appropriate to the clinical presentation. Large deletions, which are common causes some syndromes may not be reliably detected by sequencing either in panels or exome sequencing and may still need gene specific testing using the technique of MLPA though detection of these mutations through software algorithms applied to next gen sequencing approaches is quickly improving . These next gen strategies are now a lot cheaper than traditional Sanger sequencing of individual genes chosen to match the phenotype, with the likelihood that multiple genes will need to be tested sequentially when only Sanger sequencing is available.  

Table 6.1 Familial syndromes associated with increased risk of colorectal cancer[edit source]

Syndrome Gene responsible Inheritance Typical phenotype Extracolonic manifestations
Lynch syndrome* EPCAM deletion leading to epigenetic silencing of MSH2 , MLH1, MSH6 or PMS2 Autosomal dominant Early onset colorectal cancer, particularly in the proximal colon.

The incidence of adenomas is not high but those that do arise have a high risk of rapidly progressing to malignancy. Cancers display microsatellite instability

Endometrial, ovarian, gastric, pancreatic, urothelial, renal pelvic, small intestine, biliary tract, brain, sebaceous gland adenomas and keratoacanthomas
Familial adenomatous polyposis (FAP)* APC Autosomal dominant > 100 adenomas Duodenal, gastric, desmoid, brain, thyroid, hepatoblastoma
Attenuated FAP (AFAP) APC Autosomal dominant > 10 adenomas before age 30 years or 20–100 adenomas Duodenal, gastric
MUTYH-associated polyposis MUTYH Autosomal recessive Usually 20–100 adenomas but may have > 100 Duodenal, gastric
Polymerase proofreading-associated polyposis (PPAP) POLD1 or POLE Autosomal dominant 10–100 adenomas and variable number of serrated polyps Endometrial
NTHL1-associated polyposis (NAP) NTHL1 Autosomal recessive 8–50 adenomatous polyps Endometrial
Peutz-Jeghers syndrome STK11 Autosomal dominant Histologically characteristic hamartomatous polyps throughout gastrointestinal tract and mucocutaneous pigmentation Upper gastrointestinal and small intestine, breast, gynaecological, pancreas
Juvenile polyposis syndrome SMAD4 or BMPR1A Autosomal dominant Histologically characteristic hamartomatous polyps throughout gastrointestinal tract; polyps of mixed histology may also be present Upper gastrointestinal and small intestine but no evidence of excess risk for extra-gastrointestinal cancers
Serrated polyposis syndrome Unknown Unclear and low penetrance At least 5 serrated polyps proximal to the sigmoid with ≥ 2 of these > 10 mm or > 20 serrated polyps of any size but distributed throughout the colon Nil known
Cowden syndrome PTEN Autosomal dominant Some patients develop adenomas and hyperplastic polyps in addition to colonic hamartomas.

There is no evidence that all families with PTEN are at high risk of bowel cancer. Families with a history of colorectal cancer should follow screening guidelines based on their family history.

Breast, endometrial, thyroid, renal, skin lesions (trichilemmoma, papilloma). Cowden Syndrome is often associated with macrocephaly.

*Note on nomenclature Historically, eponymous names were used to refer to specific clinical phenotypes in an individual patient, but now that the genetic basis of FAP and LS is known they should be avoided.

  • Gardner Syndrome refers to classic FAP where intestinal polyposis is associated with extra-intestinal manifestations including osteomas (typically of the skull), fibromas, epidermoid cysts and desmoid tumours.
  • Muir-Torre syndrome refers to Lynch syndrome associated with sebaceous gland tumours such as sebaceous epitheliomas, sebaceous adenomas, sebaceous carcinomas and keratoacanthomas.
  • Turcot syndrome (brain tumour – polyposis syndrome) refers to the occurrence of multiple colorectal adenomas and a primary brain tumour. It can also be associated with cafe-au-lait spots. Turcot syndrome is associated with at least 2 distinct types of germline defects:
  • Type I is associated with a mutation in one of the mismatch repair genes and gliomas (predominantly astrocytomas) and accounts for about one third of cases.
  • Type 2, which accounts for two thirds of cases, is associated with a mutation in the APC gene (FAP variant) and medulloblastoma is the most common type of brain tumour.

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Principles of management[edit source]

The optimal management of individuals with, or at risk of, a familial colorectal cancer syndrome is dependent upon determining which syndrome is present. The provisional diagnosis should be based on well verified clinical and pathological data concerning the index patient and other affected members of the family. The diagnosis may ultimately be confirmed by the demonstration of a causative germline mutation. Genetic testing is highly specific for the syndromes in question, and, for most genes, highly sensitive. There remains a small group of patients and families meeting phenotypic diagnostic criteria for the various syndromes where a mutation in the relevant gene is not identified. This could be because of cryptic mutations difficult to uncover, or because another gene, yet to be discovered, is responsible. This means that phenotypic diagnoses need to be respected for management purposes even if a genotype has not been characterised.

Care is focused on the family as well as individual patients. It aims to reduce cancer morbidity and mortality by offering information about the risk of colorectal and other cancers and evidenced-based interventions to reduce this risk. There is evidence that participation in regular surveillance programs reduces cancer mortality in individuals carrying mutations causing familial adenomatous polyposis and Lynch syndrome.[5] Screening has not been shown to be beneficial for other rarer familial colorectal cancer syndromes. This is likely a result of small numbers in studied cohorts.

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Multidisciplinary approach[edit source]

Patients with these syndromes benefit from management through familial cancer clinics that include geneticists, genetic counsellors, family based databases and multidisciplinary collaboration with gastroenterologists, colorectal surgeons and pathologists. The personal history of cancer and polyps in the index patient needs to be established and, if necessary, pathology review arranged. A detailed family history (pedigree) is collected and confirmed, where possible, by obtaining histological reports, clinical records, cancer registry information and/or death certificates. A provisional diagnosis is then reached and germline genetic testing arranged with pre- and post-test genetic counselling. Based on this, the diagnosis is refined and management recommendations made.

The index patient is supported in advising family members of the diagnosis and, where available, the benefits of predictive testing and surveillance. Communication is of utmost importance in the clinic with pre- and post-test counselling of patients and clear lines of communication with treating health professionals outside the familial cancer clinic.

Family registries have been associated with reduced cancer incidence within families. State-based familial cancer registries have been established in Australia (see Supplement. State- and territory-based familial cancer registries).

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References[edit source]

  1. Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW, et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015 Feb;110(2):223-62; quiz 263 Available from:
  2. Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, et al, 2015. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. Journal of Clinical Oncology 2015;33: 209-17 Available from:
  3. Church JM. Polymerase proofreading-associated polyposis: a new, dominantly inherited syndrome of hereditary colorectal cancer predisposition. Dis Colon Rectum 2014 Mar;57(3):396-7 Available from:
  4. Weren RD, Ligtenberg MJ, Kets CM, de Voer RM, Verwiel ET, Spruijt L, et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet 2015 Jun;47(6):668-71 Available from:
  5. Barrow P, Khan M, Lalloo F, Evans DG, Hill J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg 2013 Dec;100(13):1719-31 Available from:

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