Abstract
Lynch syndrome is a hereditary cancer-predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow-up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR-proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEUROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma formation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR-deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient’s carcinogenesis subtype.
Highlights
Lynch syndrome (LS) is a hereditary disorder with an autosomal dominant transmission that primarily predisposes to colorectal and endometrial cancer, but is associated with other extra-colonic malignancies, such as stomach, small bowel, pancreatic, bladder, prostate, and biliary tract cancers [1]
LS carriers are born with germline mutations in DNA mismatch repair (MMR) genes, such as MLH1, MSH2, MSH6, and PMS2, or, more rarely, deletions in the 3 end of the EPCAM gene that lead to hypermethylation of MSH2 gene promoter
In order to optimize current surveillance programs for LS carriers, more sophisticated endoscopic techniques, such as chromoendoscopy, virtual chromoendoscopy as narrow-band imaging (NBI), could be implemented to improve the detection of adenomas compared to normal colonoscopy
Summary
Lynch syndrome (LS) is a hereditary disorder with an autosomal dominant transmission that primarily predisposes to colorectal and endometrial cancer, but is associated with other extra-colonic malignancies, such as stomach, small bowel, pancreatic, bladder, prostate, and biliary tract cancers [1]. Most commonly, MMR deficiency is an early event in tumor formation and promotes the development of precursor lesions termed MMR-deficient crypt foci (MMR-DCF), which can progress either through a non-polypoid adenomatous phase (second type of carcinogenesis) or lead directly to invasive cancer (third type of carcinogenesis), which is why colonoscopy alone does not currently seem to be sufficient for early diagnosis [40] (Figure 2). Most commonly, MMR deficiency is an early event in tumor formation and promotes the development of precursor lesions termed MMR-deficient crypt foci (MMR-DCF), which can progress either through a non-polypoid adenomatous phase (second type of carcinogenesis) or lead directly to invasive cancer (third type of carcinogenesis), which is why colonoscopy alone does5nofo1t5 currently seem to be sufficient for early diagnosis [40] (Figure 2).
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