A636P is associated with early-onset colon cancer in Ashkenazi Jews

BACKGROUND: Hereditary predisposition to colorectal cancer most often manifests itself as familial adenomatous polyposis from mutations of APC, or hereditary nonpolyposis colorectal cancer, resulting from mutations of MSH2, MLH1, MSH6, or other genes. Previously, we described a rare founder mutation MSH2*1906C > G in Ashkenazi Jews that was found in 8 of 1,345 individuals (0.6%) of Ashkenazi descent with colorectal cancer. This study seeks to characterize the proportion of individuals of Ashkenazi heritage with very early-onset colon cancer (diagnosed at age 40 or younger) that could be attributed to MSH2*1906C > G. STUDY DESIGN: We analyzed the carrier frequency of MSH2*1906C > G in paraffin samples from 31 Jewish patients age 40 or less, diagnosed with colorectal cancer at Memorial Sloan-Kettering and lymphocyte-derived DNA from 10 patients. We did not select for family history. Genotyping for MSH2*1906C > G was performed by polymerase chain reaction and restriction enzyme digestion methods. RESULTS: We detected the MSH2*1906G > C mutation in 3 of the 41 samples (7.14%) of patients who had colorectal cancer diagnosed at age 40 or younger. This incidence is significantly greater than the 8 in 1,345 (0.6%) we observed for cases of colorectal cancer in Ashkenazi Jews not selected for age (p = 0.004). CONCLUSIONS: Although very rare in the population, MSH2*I906G > C is found at an increased frequency in young Jewish patients with colorectal cancer. These results suggest that testing for the MSH2*1906G > C mutation should be included in the evaluation of Ashkenazi Jewish individuals diagnosed with early-onset colon cancer.