title: 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.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Ratner
authors.forename: Lingeng
authors.initials: L
authors.lastname: Lu
authors.forename: Marta
authors.initials: M
authors.lastname: Boeke
authors.forename: Rachel
authors.initials: R
authors.lastname: Barnett
authors.forename: Sunitha
authors.initials: S
authors.lastname: Nallur
authors.forename: Lena J
authors.initials: LJ
authors.lastname: Chin
authors.forename: Cory
authors.initials: C
authors.lastname: Pelletier
authors.forename: Rachel
authors.initials: R
authors.lastname: Blitzblau
authors.forename: Renata
authors.initials: R
authors.lastname: Tassi
authors.forename: Trupti
authors.initials: T
authors.lastname: Paranjape
authors.forename: Pei
authors.initials: P
authors.lastname: Hui
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.forename: Herbert
authors.initials: H
authors.lastname: Yu
authors.forename: Harvey
authors.initials: H
authors.lastname: Risch
authors.forename: Thomas
authors.initials: T
authors.lastname: Rutherford
authors.forename: Peter
authors.initials: P
authors.lastname: Schwartz
authors.forename: Alessandro
authors.initials: A
authors.lastname: Santin
authors.forename: Ellen
authors.initials: E
authors.lastname: Matloff
authors.forename: Daniel
authors.initials: D
authors.lastname: Zelterman
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Weidhaas
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D011905:Genes, ras; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers