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. Cancer Res; 70(16); 6509-15. ©2010 AACR.

Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women

“…In addition to familial BRCA1 and BRCA2 mutations, there are other kinds of genetic risk factors, including common genetic variants of lower penetrance 2,3 . Molecular epidemiological studies have been conducted with the candidate gene approach to identify low penetrance susceptibility genes for ovarian cancer, many of which have showed inconsistent results [4][5][6][7][8][9][10][11] . Recent genome-wide association studies (GWASs) have reported 11 new singlenucleotide polymorphisms (SNPs) that are associated with ovarian cancer risk in European populations [12][13][14][15][16][17] .…”

Estrogen withdrawal, increased breast cancer risk and the KRAS-variant

“…2 This mutation predicts an increased risk of several cancers, including non-small cell lung cancer, 2 triple negative breast cancer (TNBC) in premenopausal women 3 and ovarian cancer. [4][5][6] The KRAS-variant also predicts unique tumor biology, with tumors in KRAS-variant patients exhibiting a KRAS-addicted signature, as well as an estrogen negative, basal-like gene expression pattern. 3,5 Perhaps most powerful is the extensive evidence that the KRAS-variant is biologically functional, as exemplified by its role as a strong biomarker of response to cancer therapy.…”

Functional SNP in the microRNA-367 binding site in the 3′UTR of the calcium channel ryanodine receptor gene 3 ( RYR3 ) affects breast cancer risk and calcification

“…SNPs are the most frequent variation in the human genome, and they occur once every several hundred base pairs throughout the genome. An increasing number of 3′UTR SNPs located in miRNA binding sites have been reported to be associated with cancers (15)(16)(17) and drug response (18), presumably because of the differential binding affinities of the SNPs for miRNA. Polymorphisms in these miRNA binding sites in the 3′UTRs of target genes represent a group of genetic variations that modulate the regulatory loop between miRNAs and their target genes (18,19).…”