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Hereditary colorectal cancers, both polyposis and nonpolyposis, arise from either high-penetrance germline mutations (such as in mismatch repair genes causing Lynch syndrome), moderate-penetrance genes (such as CHEK2 or the APC I1307 variant), and low-penetrance alleles. Nevertheless, in a significant number of cases that are highly suspicious for being hereditary, no pathogenic variants are identified in the known susceptibility genes.

Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for 5% to 10% of all colorectal cancers. HNPCC includes Lynch syndrome, commonly with microsatellite unstable tumors caused by a faulty deoxyribonucleic acid (DNA) mismatch repair system, and the less clear microsatellite stable HNPCC (MSS-HNPCC), also called familial colorectal cancer type X, that does not have DNA mismatch repair deficiency. Also, not well defined is an undetermined percentage of cases that could be related to a number of low-susceptibility alleles, as well as some cases of unclear etiology that result in mismatch repair–deficient tumors but with absence of germline mutations in mismatch repair genes (Lynch-like syndrome).

Lynch Syndrome

Lynch syndrome is an autosomal dominant cancer syndrome due to germline mutations in the MMR genes MLH1, MSH2, MSH6, or PMS2. EPCAM also contributes to the pathogenesis of Lynch syndrome, as deletions at the 3′ end of EPCAM cause hypermethylation of the MSH2 promoter region. This hypermethylation leads to epigenetic silencing of MSH2 and subsequent loss of MSH2 expression.1 One in 279 individuals (0.36% of the general population) has Lynch syndrome, making it one of the most common cancer syndromes. The most commonly Lynch syndrome mutated genes in the overall population are PMS2 (1 in 714 individuals) and MSH6 (1 in 758). MLH1 (1 in 1946) and MSH2 (1 in 2841) are less common.2 Nevertheless, mutations in MLH1 and MSH2 account for over 60% of cancers related to Lynch syndrome, as they have a higher cancer penetrance than MSH6 and PMS2.3

About 3% of all colorectal cancers are related to Lynch syndrome. Besides the mentioned differences in terms of cancer risk, there are also important differences related to age at diagnosis among the different MMR genes. Thus, the mean age of colorectal cancer diagnosis in patients with MLH1 and MSH2 (including EPCAM) mutations is 44 years old, while it is later for MSH6 (42 to 69 years old), as well as for PMS2 (61 to 66 years old).4

In addition to being implicated in colorectal cancer, Lynch syndrome carries an increased risk of extracolonic cancers. Thus, 2% of all endometrial cancers are related to Lynch syndrome. About 10% to 15% of all inherited ovarian cancers and a not well-defined proportion of inherited gastric cancers are also due to Lynch syndrome. Other Lynch syndrome–related cancers include biliary tract, uroepithelial and kidney, and central nervous system.5 In terms of location, Lynch syndrome–associated colorectal cancers are more often right-sided, or proximal to the splenic ...

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