Mutation spectrum and risk of colorectal cancer in African American families with Lynch Syndrome

abstract
 

Background & Aims

African Americans (AAs) have the highest incidence and mortality of colorectal cancer (CRC) in the United States (US). Few data are available on genetic and non-genetic risk factors for CRC among AAs. Little is known about cancer risks and mutations in mismatch repair (MMR) genes in AAs with the most common inherited CRC syndrome, Lynch syndrome. We aimed to characterize phenotype, mutation spectrum, and risk of CRC in AAs with Lynch Syndrome.

Methods

We performed a retrospective study of AAs with mutations in MMR genes (MLH1, MSH2, MSH6, and PMS2) using databases from 13 US referral centers. We analyzed data on personal and family histories of cancer. Modified segregation analysis conditioned on ascertainment criteria was used to estimate age- and sex-specific CRC cumulative risk studying members of the mutation-carrying families.

Results

We identified 51 AA families with deleterious mutations that disrupt function of the MMR gene product: 31 in MLH1 (61%), 11 in MSH2 (21%), 3 in MSH6 (6%), and 6 in PMS2 (12%); 8 mutations were detected in more than 1 individual and 11 have not been previously reported. In the 920 members of the 51 families with deleterious mutations, the cumulative risks of CRC at an age of 80 y were estimated to be 36.2% (95% confidence interval [CI], 10.5%–83.9%) for men and 29.7% (95% CI, 8.31%–76.1%) for women. CRC risk was significantly higher among individuals with mutations in MLH1 or MSH2 (hazard ratio, 13.9; 95% CI, 3.44–56.5).

Conclusions

We estimate the cumulative risk for CRC in AAs with MMR gene mutations to be similar to that of individuals of European descent with Lynch syndrome. Two-thirds of mutations were found in MLH1—some were found in multiple individuals and some have not been previously reported. Differences in the mutation spectrum are likely to reflect the genetic diversity of this population.