Ovarian cancer risk is associated with a common variant in the promoter sequence of the mismatch repair gene MLH1

Objectives: Inherited mutations in the MLH1 gene are associated with a proportion of families with the hereditary non-polyposis colon cancer syndrome (HNPCC). The cardinal features of the syndrome are a predisposition to colon, endometrial and ovarian cancers. Recently, it has been shown that a non-coding polymorphic variant in MLH1 (G>A nt-93) predisposes to colon and endometrial cancer, but with much reduced penetrance. We sought to establish whether or not this polymorphic variant also predisposes to ovarian cancer. Methods: We genotyped 899 women with invasive ovarian cancer and 931 controls for the G>A nt-93 variant. Results: The presence of the variant was associated with a modest, but highly significant risk of ovarian cancer (OR = 1.5; 95% CI 1.3-1.9; p = 0.00005). The association was present in cancers of all histologies except clear cell, and in all ethnic groups. Conclusions: The G>A nt-93 variant of the MLH1 gene is associated with an increased risk of invasive ovarian cancer.