Colorectal and endometrial cancer risk and age at diagnosis in BLM^Ash mutation carriers

Background: Biallelic BLM gene mutation carriers are at an increased risk for cancer, including colorectal cancer (CRC). Whether heterozygous BLM gene mutations confer an increased cancer risk remains controversial. Objectives: To evaluate CRC and endometrial cancer risk in BLM heterozygous mutation carriers. Methods: Ashkenazi Jews at high risk for colon or endometrial cancer, and endometrial cancer cases unselected for family history, were genotyped for the BLMA^sh predominant mutation. Results: Overall, 243 high-risk individuals were included: 97 men with CRC (55.12 ± 12.3 years of age at diagnosis), 109 women with CRC (56.5 ± 13.7 years), 32 women with endometrial cancer (58.25 ± 13.4 years) and 5 women with both CRC and endometrial cancer. In addition, 120 unselected Ashkenazi women with endometrial cancer (64.2 ± 11.58 years) were genotyped. The BLMA^sh mutation was present in 4/243 (1.65%) of high-risk patients; 2/208 with CRC (0.97%) 2/35 with endometrial cancer (5.4%), and 1/120 unselected endometrial cancer patients (0.84%). Notably, in high-risk cases, BLMA^sh mutation carriers were diagnosed at a younger age (for CRC 47.5 ± 7.8 years, P = 0.32; endometrial cancer 49.5 ± 7.7 years, P = 0.36) compared with non-carriers. Conclusions: Ashkenazi Jews at high risk for CRC and endometrial cancer, and women with endometrial cancer have a higher rate of BLMA^sh heterozygous mutation compared with the general population. BLMA^sh heterozygous mutation carriers are diagnosed with CRC and endometrial cancer at a younger age compared to non-carriers. These observations should be validated and the possible clinical implications assessed.