The Relationship Between Eight GWAS‐Identified Single‐Nucleotide Polymorphisms and Primary Breast Cancer Outcomes

• Published in: The oncologist (Dayton, Ohio) Ohio), 2013-05, Vol.18 (5), p.493-500
• Main Authors: Bayraktar, Soley, Thompson, Patricia A., Yoo, Suk‐Young, Do, Kim‐anh, Sahin, Aysegul A., Arun, Banu K., Bondy, Melissa L., Brewster, Abenaa M.
• Format: Article
• Language: English
• Subjects: 17q23; Adult; Aged; Breast Cancer; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Disease-Free Survival; European Continental Ancestry Group - genetics; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Middle Aged; Neoplasm Staging; Polymorphism, Single Nucleotide - genetics; Prognosis; Proportional Hazards Models; Risk Factors; Single‐nucleotide polymorphisms; TNRC9; Treatment Outcome
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2012-0419

Learning Objectives Describe the results of genome‐wide association studies (GWAS) that have identified genetic variants associated with breast cancer risk. Discuss whether genetic risk variants identified through genome‐wide association studies (GWAS) are also associated with breast cancer prognosis. Describe molecular mechanisms through which germline genetic variants may influence breast cancer survival. Background. Several single‐nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome‐wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease‐free survival (DFS) and overall survival (OS) rates. Patients and Methods. A cohort of 739 white women with early‐stage breast cancer was genotyped for eight GWAS‐identified SNPs (rs2981582, rs1219648 [FGFR2], rs3803662, rs12443621, rs8051542 [TOX3], rs999737 [RAD51L1], rs6504950 [17q23], and rs4973768 [3p24]). Relationships between SNPs and breast cancer outcomes were evaluated using Cox proportional hazard regression models. The cumulative effects of SNPs on breast cancer outcomes were assessed by computing the number of at‐risk genotypes. Results. At a median follow‐up of 121 months (range: 188–231 months) for survivors, 237 deaths (32%) and 186 breast cancer events (25%) were identified among the 739 patients. After adjusting for age, clinical stage, and treatment, rs12443621 (16q12; p = .03) and rs6504950 (17q23; p = .008) were prognostic for OS but not DFS. A higher risk for death was also found in the multivariable analysis of patients harboring three or four at‐risk genotypes of the GWAS SNPs compared to patients carrying two or less at‐risk genotypes (hazard ratio: 1.60, 95% confidence interval: 1.23–2.24; p = .0008). Conclusion. The study results suggest that previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), may influence breast cancer prognosis or comorbid conditions associated with overall survival. The precise molecular mechanisms through which these risk SNPs, as well as others that were not included in the analysis, influence clinical outcomes remain to be determined. Several single‐nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome‐wide association studies. This study investigated the association of eight risk SNPs with breast cancer disease‐free survival and overall surviv