A KRAS-variant as a biomarker of ovarian cancer risk.

Abstract

5016 Background: Ovarian cancer is the single most deadly form of women's cancer, largely due to a lack of known risk factors or genetic markers. The KRAS oncogene and altered levels of the microRNA let-7 are associated with an increased risk of developing solid tumors. We investigated the association of a single nucleotide variant (rs61764370), referred to as the KRAS-variant, previously shown to disrupt a let-7 microRNA binding site in the KRAS oncogene 1, and ovarian cancer risk. Methods: Specimens were obtained and tested for the presence of the KRAS-variant from nonselected ovarian cancer patients in three independent cohorts (n = 457), from two independent ovarian case-control studies (n = 866), and from ovarian cancer patients with hereditary breast and ovarian cancer (HBOC) syndrome (n = 58) as well as in their family members. Results: Our results indicate that the KRAS-variant is associated with greater than 25% of non-selected ovarian cancer cases, and is a marker for a significant increased risk of developing ovarian cancer as confirmed by two independent case control analyses. The KRAS-variant was also identified in 60% of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. Furthermore, the KRAS-variant predicted significantly worse outcome from ovarian cancer for its carriers. Conclusions: These findings strongly support the hypothesis that the KRAS-variant is a genetic marker of an increased risk of developing ovarian cancer, and suggests that the KRAS- variant may be a new biomarker of risk for HBOC families without other known genetic abnormalities. In addition, the KRAS-variant predicts for the most deadly ovarian cancers, which are likely the most important to prevent or catch early. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MiraDx