Hereditary and Familial Colon Cancer
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
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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.