A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk

Abstract

Ovarian cancer (OC) is the single most deadly form of women's cancer, typically presenting as an advanced disease at diagnosis in part due to a lack of known risk factors or genetic markers of risk. The KRAS oncogene and altered levels of the microRNA (miRNA) let-7 are associated with an increased risk of developing solid tumors. In this study, we investigated a hypothesized association between an increased risk of OC and a variant allele of KRAS at rs61764370, referred to as the KRAS-variant, which disrupts a let-7 miRNA binding site in this oncogene. Specimens obtained were tested for the presence of the KRAS-variant from nonselected OC patients in three independent cohorts, two independent ovarian case-control studies, and OC patients with hereditary breast and ovarian cancer syndrome (HBOC) as well as their family members. Our results indicate that the KRAS-variant is associated with more than 25% of nonselected OC cases. Further, we found that it is a marker for a significant increased risk of developing OC, as confirmed by two independent case-control analyses. Lastly, we determined that the KRAS-variant was present in 61% of HBOC patients without BRCA1 or BRCA2 mutations, previously considered uninformative, as well as in their family members with cancer. Our findings strongly support the hypothesis that the KRAS-variant is a genetic marker for increased risk of developing OC, and they suggest that the KRAS-variant may be a new genetic marker of cancer risk for HBOC families without other known genetic abnormalities.

Figure 1. The KRAS-variant is found frequently in patients with ovarian cancer compared to controls

Patients from three separate cohorts were tested for the presence of the KRAS-variant and frequency of carriers depicted with the number tested in parentheses.

Figure 2. An HBOC Family with the KRAS-variant

Circle symbols are women, squares are men. A black area within the symbol indicates the person had cancer. A line through the symbol indicates the person has died. d. means dead and lists the age. dx. means diagnosed with and lists the age. Red star indicates tested for the KRAS-variant and a carrier.

Figure 3. KRAS-variant Carrying Families Differ from BRCA Families

Cancer types and basic demographics in KRAS-variant (green) versus BRCA1 and BRCA2 carrying HBOC families. The KRAS-variant families are less likely to be Jewish (Ashkenazi status not known) than BRCA1 mutant families (p =0.003), more likely to have a family history of lung cancer as compared to BRCA2 mutant families (p =0.02), and ovarian cancer patients carrying the KRAS-variant are significantly older at the time of diagnosis than BRCA1 mutant patients with ovarian cancer (p =0.006).