A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk.
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.
Ratner
Elena
E
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Lu
Lingeng
L
Boeke
Marta
M
Barnett
Rachel
R
Nallur
Sunitha
S
Chin
Lena J
LJ
Pelletier
Cory
C
Blitzblau
Rachel
R
Tassi
Renata
R
Paranjape
Trupti
T
Hui
Pei
P
Godwin
Andrew K
AK
Yu
Herbert
H
Risch
Harvey
H
Rutherford
Thomas
T
Schwartz
Peter
P
Santin
Alessandro
A
Matloff
Ellen
E
Zelterman
Daniel
D
Slack
Frank J
FJ
Weidhaas
Joanne B
JB
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*
D014408:Biomarkers, Tumor; D005819:Genetic Markers