Association between a germline OCA2 polymorphism at chromosome 15q13.1 and estrogen receptor-negative breast cancer survival

Elizabeth M. Azzato, Jonathan Tyrer, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Rüdiger Schulz-Wendtland, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, Roger L. Milne, José Ignacio Arias, Primitiva Menéndez, Javier Benítez, Jenny Chang-Claude, Rebecca Hein, Shan Wang-Gohrke, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl BlomqvistSara Margolin, Arto Mannermaa, Veli Matti Kosma, Vesa Kataja, Jonathan Beesley, Xiaoqing Chen, Georgia Chenevix-Trench, Fergus J. Couch, Janet E. Olson, Zachary S. Fredericksen, Xianshu Wang, Graham G. Giles, Gianluca Severi, Laura Baglietto, Melissa C. Southey, Peter Devilee, Rob A.E.M. Tollenaar, Caroline Seynaeve, Montserrat García-Closas, Jolanta Lissowska, Mark E. Sherman, Kelly L. Bolton, Per Hall, Kamila Czene, Angela Cox, Ian W. Brock, Graeme C. Elliott, Malcolm W.R. Reed, David Greenberg, Hoda Anton-Culver, Argyrios Ziogas, Manjeet Humphreys, Douglas F. Easton, Neil E. Caporaso, Paul D.P. Pharoah

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Abstract

Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

Original languageEnglish
Pages (from-to)650-662
Number of pages13
JournalJournal of the National Cancer Institute
Volume102
Issue number9
DOIs
Publication statusPublished - 1 May 2010
Externally publishedYes

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