Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario

Abstract Background Several DNA mismatch repair (MMR) genes, responsible for the majority of Lynch Syndrome cancers, have been identified, predominantly MLH1 and MSH2, but the risk associated with these mutations is still not well established. The aim of this study is to provide population-based estimates of the risks of colorectal cancer (CRC) by gender and mutation type from the Ontario population. Methods We analyzed 32 families segregating MMR mutations selected from the Ontario Familial Colorectal Cancer Registry and including 199 first-degree and 421 second-degree relatives. The cumulative risks were estimated using a modified segregation-based approach, which allows correction for the ascertainment of the Lynch Syndrome families and permits account to be taken for missing genotype information. Results The risks of developing CRC by age 70 were 60% and 47% among men and women carriers of any MMR mutation, respectively. Among MLH1 mutation carriers, males had significantly higher risks than females at all ages (67% vs. 35% by age 70, p-value = 0.02), while the risks were similar in MSH2 carriers (about 54%). The relative risk associated with MLH1 was almost constant with age (hazard ratio (HR) varied between 5.5-5.1 over age 30–70), while the HR for MSH2 decreased with age (from 13.1 at age 30 to 5.4 at age 70). Conclusion This study provides a unique population-based study of CRC risks among MSH2/MLH1 mutation carriers in a Canadian population and can help to better define and understand the patterns of risks among members of Lynch Syndrome families