Recently identified colon cancer predispositions: MYH and MSH6 mutations

Abstract

Single-gene germline mutations conferring a high lifetime risk of colorectal cancer (CRC) account for up to 6% of all CRC cases. The most widely studied monogenic colorectal cancer syndromes include familial adenomatous polyposis (FAP) and Lynch syndrome. However, additional syndromes continue to be defined and new predisposition genes are continuing to be identified. Most recently, MYH-associated polyposis (MAP) and an "atypical Lynch syndrome" related to the presence of MSH6 mutations have been linked to an increased risk of CRC. In this review, we summarize basic information related to these newly recognized gene mutations, including the accumulating data on the prevalence and penetrance of deleterious mutations, as well as the management options for identified carriers and their families. Recognizing these heritable syndromes is essential and predictive genetic testing will continue to transform the field of cancer risk assessment by offering the opportunity to focus on more precise risk management and cancer prevention.

Figure 1. CRC Risk associated with monoallelic MYH variants*

*Funnel plot of OR of CRC risk associated with monoallelic Y165C and G382D MYH variants, under a fixed-effects model. Studies are plotted in order of decreasing variance of the log (Odds Ratio). Horizontal lines represent 95% Confidence Intervals (CI). Each box represents the Odds Ratio (OR) point estimate, and its area is proportional to the weight of the study. The diamond and broken line represent the overall summary estimate, with the 95% CI given by the width of the diamond. The unbroken vertical line is at the null value (OR 1.0). Reprinted with permission.