Encyclopedia of Cancer, 2015
Hereditary nonpolyposis colorectal cancer; HNPCC
Lynch syndrome is an autosomal dominantly inherited cancer susceptibility syndrome, characterized by cancers of multiple anatomic sites, of which colorectal cancer (CRC) is the most common. Mismatch repair (MMR) genes, inclusive of MLH2, MLH1, PMS2, and MSH6, in their mutant form are causal for the cancer phenotype. More recently, it has been found that deletions in the EPCAM gene can silence MSH2 (Ligtenberg et al. 2009; Lynch et al. 2011). Lynch syndrome appears to show genotypic and phenotypic heterogeneity. MSH2 mutations may predispose to a greater frequency of extracolonic cancers, while mutations in MSH6 may result in a predominance of gynecologic cancer, particularly endometrial carcinoma, so that CRC may not pose the primary basis for Lynch syndrome diagnosis. Lynch syndrome is the most commonly occurring CRC disorder.
Molecular genetic findings have enabled hereditary CRC to be divided into two groups: (i) tumors that show microsatellite instability (MSI); occur more frequently in the right colon; have diploid DNA; harbor characteristic mutations such as transforming growth factor beta Type II receptor, BAX26, or MMR; and behave indolently, of which the Lynch syndrome is an example, and (ii) tumors with chromosomal instability (CIN), which tend to be left sided; show aneuploid DNA; harbor characteristic mutations such as K-ras, APC, or p53; and behave aggressively, of which familial adenomatous polyposis (FAP) is an example.
Characteristics (clinical, molecular, and pathology): Affected individuals inherit a mutation in one of the MMR gene alleles. When a second mutation is acquired in the wild-type allele, the target cell is less able to repair DNA mismatch errors. Tumors composed of such cells characteristically manifest MSI. Most of the tumors arising in the Lynch syndrome are MSI+, while about 15 % of apparently sporadic CRCs are MSI+. This is exceedingly interesting in that those sporadic MSI+ tumors have clinical pathologic features similar to those observed in the Lynch syndrome (Chung and Rustgi 1995).
Prior to molecular genetic breakthroughs, one was required to depend upon the cardinal features of the Lynch syndrome, since there were no premonitory signs or biomarkers to guide diagnosis. These cardinal features are as follows:
- The inheritance pattern is autosomal dominant.
- Gene penetrance for CRC is ~85–90 %.
- Mutation carriers develop CRC at an early age (~45 years).
- Most (~70 %) CRCs arise proximal to the splenic flexure.
- Multiple CRCs, both synchronous and metachronous, are common.
- Accelerated carcinogenesis is present.
- The prognosis is better than for sporadic CRC.
- The pathology features of CRC are often distinguishable (but not pathognomonic) and include poor differentiation, increased signet cells, medullary features, peritumoral lymphocytic infiltration, Crohn’s-like reaction, and an increased frequency of tumor-infiltrating lymphocytes (TILs) admixed with tumor cells.
- There is an increased risk for malignancy in certain extracolonic sites, including the endometrium, ovary, stomach, small bowel, hepatobiliary tract, pancreas, renal pelvis, prostate, and breast. The MuirTorre syndrome variant includes sebaceous skin cancers, and the Turcot’s syndrome variant includes glioblastomas.
Fig. 1. Lynch syndrome: indications for testing. CRC colorectal cancer, EGAPP Evaluation of Genomics Applications in Practice and Prevention Working Group, HNPCC hereditary nonpolyposis colorectal cancer, IHC immunohistochemistry, LS Lynch syndrome, MMR mismatch repair, MSI-H microsatellite instability-high, MSI-L microsatellite instability-low, MSS microsatellite stable
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- Chung DC, Rustgi AK (1995) DNA mismatch repair and cancer. Gastroenterology 109:1685–1699 Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (2009) Rec-
- ommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med 11:35–41
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- Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ (1966) Hereditary factors in cancer: study of two large Midwestern kindreds. Arch Intern Med 117:206–212
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