From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome

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.

Keywords: CRC; Lynch syndrome; MMR genes; early detection.

Figure 1

Cumulative risk of developing cancer in patients with LS according to the type of mismatch repair gene mutation by the age of 80. Dark and light blue bars indicate the lower and upper cumulative risk, respectively, for each cancer type. The red numbers above each bar represent the estimated mean age at presentation for each cancer type. Asterisks (*) and double asterisks (**) indicate that limited or no data are available for the mean age at presentation and the cumulative cancer risk, respectively.

Figure 2

Three different models of colorectal carcinogenesis in Lynch syndrome patients.

Figure 3

List of potential molecular markers that could be analyzed non-invasively for methylation or mutational status by testing distant media (stool or blood).