Common germline polymorphisms in COMT,CYP19A1, ESR1, PGR,SULT1E1 and STS and survival after a diagnosis of breast cancer |
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| Authors: | Miriam S. Udler Elizabeth M. Azzato Catherine S. Healey Shahana Ahmed Karen A. Pooley David Greenberg Mitul Shah Andrew E. Teschendorff Carlos Caldas Alison M. Dunning Elaine A. Ostrander Neil E. Caporaso Douglas Easton Paul D. Pharoah |
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| Affiliation: | 1. Strangeways Research Laboratory, Departments of Public Health and Primary Care and Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, United Kingdom;2. Cancer Genetic Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;3. The first two authors contributed equally to this work.;4. Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD;5. Eastern Cancer Registration and Information Centre, Unit C‐Magog Court, Shelford Bottom, Cambridge CB22 3AD, United Kingdom;6. Cancer Research UK, Cambridge Research Institute, and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom;7. Medical Genomics Group, Paul O'Gorman Building, UCL Cancer Institute, University College London, London WC1E 6BT, United Kingdom;8. Fax: +44 (0) 1223 411609. |
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| Abstract: | Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population‐based case–control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p = 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR = 0.80 95% CI: 0.69–0.95, p = 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p = 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted. © 2009 UICC |
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| Keywords: | breast cancer survival polymorphism genetic epidemiology |
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