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

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 (GA 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.We genotyped 899 women with invasive ovarian cancer and 931 controls for the GA nt-93 variant.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.The GA nt-93 variant of the MLH1 gene is associated with an increased risk of invasive ovarian cancer.