Gastroenterology

Gastroenterology

Volume 138, Issue 6, May 2010, Pages 2044-2058
Gastroenterology

Hereditary and Familial Colon Cancer

https://doi.org/10.1053/j.gastro.2010.01.054Get rights and content

Between 2% to 5% of all colon cancers arise in the setting of well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance. A number of less penetrant, but possibly more frequent susceptibility genes have been identified for this level of inheritance. Clarification of predisposing genes allows for accurate risk assessment and more precise screening approaches. This review examines the colon cancer syndromes, their genetics and management, and also the common familial colon cancers with current genetic advances and screening guidelines.

Section snippets

Inherited CRC Syndromes With Adenomatous Polyps

The syndromes of CRC are defined on the basis of clinical, pathological, and, more recently, genetic findings. Conditions that express adenomatous polyps include Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), familial adenomatous polyposis (FAP), attenuated FAP, and MUTYH-associated polyposis (MAP). Hamartomatous polyps are the primary lesions in Peutz-Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS). Finally, hyperplastic polyposis (HPP) is an unusual

Lynch Syndrome

Individuals with Lynch syndrome are predisposed to various types of cancers, especially colon and endometrial (see Table 1).3 The syndrome accounts for 2%–4% of all CRCs.4 Although affected individuals can develop colonic adenomas with greater frequency than the general population, polyposis is rare. Lifetime CRC risk is estimated to be 50%–80%.5

Colon cancers and polyps arise in Lynch syndrome at a younger age of onset and a more proximal location compared to sporadic neoplasms. Histologically,

FAP: Classic and Attenuated

FAP is the second-most common inherited CRC syndrome, with a prevalence of 1 in 10,000 individuals. Characteristic features of FAP include development of hundreds to thousands of colonic adenomas beginning in early adolescence, and inevitable CRC in untreated individuals. The average age of CRC diagnosis if untreated is 39 years; 7% develop CRC by age 21 and 95% by age 50. Attenuated FAP is a less-severe form of the disease, characterized by an average 69% lifetime risk of CRC, an average of

MAP

MAP is characterized by the presence of adenomatous polyposis of the colorectum and an increased risk of CRC. MAP is caused by biallelic mutations in MUTYH (also referred to as MYH) (Table 1). The colonic phenotype of MAP mimics attenuated FAP, including a propensity for proximal colonic neoplasms.36 Colonic polyposis typically occurs by the time patients reach their 40s, although polyps and cancer can occur at earlier ages. Biallelic MUTYH mutations have also been found in individuals with

Hamartomatous Polyposis Conditions

PJS and JPS are hamartomatous polyposis conditions that are both associated with an increased risk for colorectal and other malignancies40 (Table 1). There are several other hamartomatous polyposis conditions that are very rare and confer little, if any, colon cancer risk. Cowden syndrome is one of these and it arises from mutations of PTEN.41

The characteristic gastrointestinal lesions in PJS are small bowel, histologically distinctive hamartomatous polyps (96% of PJS patients).42 Gastric and

HPP

HPP is a rare condition characterized by multiple and/or large hyperplastic polyps of the colon. The etiology of HPP is unknown. The World Health Organization's criteria for HPP include 30 cumulative hyperplastic polyps of any size distributed throughout the colon (the number 20 is now often used46); ≥5 hyperplastic polyps proximal to the sigmoid colon with at least two >10 mm in diameter; or at least 1 hyperplastic colonic polyp in an individual with a first-degree relative with HPP. Sessile

Common Familial Colorectal Cancers

Inherited forms of CRC account for as much as 30% of all CRC cases.2 Several different categories of less-penetrant, but potentially more common, causes of susceptibility have become apparent, based on family history and population studies (Figure 1). These include high-risk familial, nonsyndromic colon cancers and common familial-risk colon cancers, which are defined by family history. Population studies have also identified genetic factors associated with increased risk for CRC that include

Conclusion

Analysis of CRC risk needs to be included in mainstream clinical practice. A detailed analysis of family history is a fundamental component of this process; it is not only important for identifying patients that are at high risk for CRC (Table 2) and should receive genetic counseling, but also essential for identifying individuals with moderate risk that should receive more aggressive screening. Genetic features associated with moderate risk of CRC susceptibility will in the future expand risk

References (101)

  • M. Herraiz et al.

    Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations

    Clin Gastroenterol Hepatol

    (2007)
  • S.P. Cleary

    Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study

    Gastroenterology

    (2009)
  • K.S. Boparai et al.

    Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis

    Gastroenterology

    (2008)
  • A. Gammon et al.

    Hamartomatous polyposis syndromes

    Best Pract Res Clin Gastroenterol

    (2009)
  • E. Chow et al.

    Hyperplastic polyposis syndrome: phenotypic presentations and the role of MBD4 and MYH

    Gastroenterology

    (2006)
  • J.R. Jass

    Gastrointestinal polyposes: clinical, pathological and molecular features

    Gastroenterol Clin North Am

    (2007)
  • A. Adler et al.

    Narrow-band versus white-light high definition television endoscopic imaging for screening colonoscopy: a prospective randomized trial

    Gastroenterology

    (2009)
  • L.E. Johns et al.

    A systematic review and meta-analysis of familial colorectal cancer risk

    Am J Gastroenterol

    (2001)
  • D. Daley et al.

    Identification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study

    Am J Hum Genet

    (2008)
  • S. Winawer et al.

    Colorectal cancer screening and surveillance: clinical guidelines and rationale—update based on new evidence

    Gastroenterology

    (2003)
  • R.S. Houlston et al.

    Polymorphisms and colorectal tumor risk

    Gastroenterology

    (2001)
  • J.T. Wijnen et al.

    Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome

    Gastroenterology

    (2009)
  • E. Tulupova et al.

    Do polymorphisms and haplotypes of mismatch repair genes modulate risk of sporadic colorectal cancer?

    Mutat Res

    (2008)
  • A. Roff et al.

    A novel SNP in a vitamin D response element of the CYP24A1 promoter reduces protein binding, transactivation, and gene expression

    J Steroid Biochem Mol Biol

    (2008)
  • P. Lichtenstein et al.

    Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland

    N Engl J Med

    (2000)
  • H.T. Lynch et al.

    Hereditary colorectal cancer

    N Engl J Med

    (2003)
  • H. Hampel et al.

    Feasibility of screening for Lynch syndrome among patients with colorectal cancer

    J Clin Oncol

    (2008)
  • C.M. Ribic et al.

    Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer

    N Engl J Med

    (2003)
  • H. Hampel et al.

    Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients

    Cancer Res

    (2006)
  • A.K. Rustgi

    The genetics of hereditary colon cancer

    Genes Dev

    (2007)
  • F. Kastrinos et al.

    Risk of pancreatic cancer in families with Lynch syndrome

    JAMA

    (2009)
  • P. Peltomaki et al.

    Mutations associated with HNPCC predisposition—update of ICG-HNPCC/INSiGHT mutation database

    Dis Markers

    (2004)
  • J. Plaschke et al.

    Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium

    J Clin Oncol

    (2004)
  • L. Senter et al.

    The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations

    Gastroenterology

    (2008)
  • M.E. Kovacs et al.

    Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome

    Hum Mutat

    (2009)
  • M.J. Ligtenberg et al.

    Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1

    Nat Genet

    (2009)
  • R.C. Niessen et al.

    Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome

    Genes Chromosomes Cancer

    (2009)
  • D.A. Stupart et al.

    Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation

    Colorectal Dis

    (2009)
  • K.M. Schmeler et al.

    Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome

    N Engl J Med

    (2006)
  • J.S. Kwon et al.

    Cost-effectiveness analysis of prevention strategies for gynecologic cancers in Lynch syndrome

    Cancer

    (2008)
  • Clinical practice guidelines in oncology: colorectal cancer screening

  • S. Bulow et al.

    Duodenal adenomatosis in familial adenomatous polyposis

    Gut

    (2004)
  • D. Speake et al.

    Desmoid tumours in patients with familial adenomatous polyposis and desmoid region adenomatous polyposis coli mutations

    Br J Surg

    (2007)
  • A.L. Knudsen et al.

    Attenuated familial adenomatous polyposis (AFAP)A review of the literature

    Fam Cancer

    (2003)
  • F.J. Hes et al.

    Somatic APC mosaicism: an underestimated cause of polyposis coli

    Gut

    (2008)
  • J.G. Guillem et al.

    ASCO/SSO review of current role of risk-reducing surgery in common hereditary cancer syndromes

    J Clin Oncol

    (2006)
  • D.W. Rattner et al.

    Defining the criteria for local resection of ampullary neoplasms

    Arch Surg

    (1996)
  • M.C. Gallagher et al.

    Surveillance and management of upper gastrointestinal disease in familial adenomatous polyposis

    Fam Cancer

    (2006)
  • S.J. Lubbe et al.

    Clinical implications of the colorectal cancer risk associated with MUTYH mutation

    J Clin Oncol

    (2009)
  • S. Vogt et al.

    Expanded extracolonic tumor spectrum in MUTYH-associated polyposis

    Gastroenterology

    (2009)
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    Conflicts of interest The authors disclose the following: Dr Burt is a consultant for Myriad Genetics and Archimedes, Inc. The remaining authors disclose no conflicts.

    Funding This research was supported by National Cancer Institute grants P01-CA073992 (RWB), R01-CA040641 (RWB) and by the Huntsman Cancer Foundation.

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