Cancer risks for MLH1 and MSH2 mutation carriers

Abstract

We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.

Figure 1

The estimated distribution of colorectal cancer cumulative risk to age 70 years for each combination of gene and sex. For example, from the leftmost black bar, 17% of male MSH2 mutation carriers are estimated to have a less than 10% chance of developing colorectal cancer by age 70 years.

Figure 2

Colorectal cancer cumulative risks for males (A) and females (B) and endometrial cancer cumulative risks for females (C). Cumulative risks are for MLH1 mutation carriers (unbroken lines), MSH2 mutation carriers (dashed lines) and the general population (dotted lines) living in Australia and New Zealand (light grey), Canada (dark grey) and USA (black).