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  • 1
    Keywords: CANCER ; SURVIVAL ; RISK ; FAMILY ; ASSOCIATION ; SUSCEPTIBILITY ; BREAST-CANCER ; MUTATIONS ; MUTATION CARRIERS ; susceptibility loci ; GENOME-WIDE ASSOCIATION ; CONSORTIUM
    Abstract: Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95-1.10), serous EOC (OR = 1.08, 95% CI: 0.98-1.18), familial EOC (OR = 1.09, 95% CI: 0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88-1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93-1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted.
    Type of Publication: Journal article published
    PubMed ID: 21385923
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  • 2
    Keywords: CANCER ; MODEL ; PATHWAY ; PATHWAYS ; ALGORITHM ; RISK ; GENE ; GENES ; SAMPLE ; DNA ; FAMILY ; BIOMARKERS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; VARIANTS ; STAGE ; HEALTH ; BRCA1 ; ovarian cancer ; OVARIAN-CANCER ; WOMEN ; MUTATION ; SNP ; cancer risk ; MUTATIONS ; MULTIVARIATE ; UNITED-STATES ; REPLICATION ; VALIDITY ; inflammation ; STATES ; ONCOLOGY ; FAMILIES ; VARIANT ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; ARRAY ; METAANALYSIS ; SINGLE-NUCLEOTIDE POLYMORPHISMS ; biomarker ; analysis ; HAPLOTYPE ; USA ; CANDIDATE ; cancer research ; CANCER-RISK ; COMMUNITY ; REPAIR GENES ; RATIO ; CONSORTIUM ; NUCLEOTIDE ; STATE ; genetic variants ; COLLABORATIVE ANALYSIS ; HORMONAL FACTORS ; STATES CASE-CONTROL
    Abstract: Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States, but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low-penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNP) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (P = 0.002) with a 〈 25% chance of being a false-positive finding (q value = 0.240). Using a multivariate model search algorithm over 11 IL18 tagging SNPs, we found that the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (odds ratio, 1.24; 95% confidence interval, 1.06-1.45). In a replication stage, 12 independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (odds ratio, 0.99; 95% confidence interval, 0.94-1.05) when data from the 12 OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial North Carolina Ovarian Cancer Study data. This analysis shows the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. (Cancer Epidemiol Biomarkers Prev 20081-17(12):3567-72)
    Type of Publication: Journal article published
    PubMed ID: 19064572
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