Journal of the National Cancer Institute Advance Access originally published online on June 30, 2009
JNCI Journal of the National Cancer Institute 2009 101(14):1012-1018; doi:10.1093/jnci/djp167
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© The Author 2009. Published by Oxford University Press.
ARTICLES |
Risk of Estrogen Receptor–Positive and –Negative Breast Cancer and Single–Nucleotide Polymorphism 2q35-rs13387042
Affiliations of authors: Genetic and Molecular Epidemiology Group (RLM) and Human Genetics Group (JBe), Spanish National Cancer Research Centre [CNIO], Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras [CIBERER], Madrid, Spain (JBe); Department of Obstetrics and Gynecology (HN, TH), Department of Clinical Genetics (KA), and Department of Oncology (CB), Helsinki University Central Hospital, Helsinki, Finland; Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo, Spain (JIA); Servicio de Oncología Médica, Hospital Universitario La Paz, Madrid, Spain (MPZ); Department of Obstetrics and Gynecology (BB) and Institute of Human Genetics (CRB), University of Heidelberg, Heidelberg, Germany; Molecular Epidemiology Group (BB) and Division of Cancer Epidemiology (JC-C), German Cancer Research Center [DKFZ]), Heidelberg, Germany; Department of Gynaecology and Obstetrics, Technical University of Munich, Munich, Germany (AMe); Department of Gynaecology and Obstetrics, Clinical Center University of Cologne, Köln, Germany (RKS); Institute for Cancer Studies (AC, IB, GE) and Academic Unit of Surgical Oncology (MWRR), Sheffield University Medical School, Sheffield, UK; Centre for Molecular, Environmental, Genetic and Analytic Epidemiology (JLH, DRE) and Department of Pathology (MCS, LS), University of Melbourne, Victoria, Australia; Department of Laboratory Medicine and Pathology (FJC, XW) and Department of Health Sciences Research (JEO, ZF), Mayo Clinic, Rochester, MN; Department of Obstetrics and Gynaecology (TD, PS, PHi, NVB, MBe) and Department of Radiation Oncology (MBr, NVB), Hannover Medical School, Hannover, Germany; Department of Human Genetics (PD), Department of Pathology (PD), Department of Clinical Genetics (CJvA), and Department of Surgery (RAEMT), Leiden University Medical Centre, Leiden, the Netherlands; Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, the Netherlands (CS); Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden (PHa, KC); Human Genetics Laboratory, Genome Institute of Singapore, Singapore (JLi, YL); Department of Oncology (SA, AMD, MM, PDPP), Department of Public Health and Primary Care (PDPP), University of Cambridge, Cambridge, UK; Division of Genetics and Population Health (GC-T, JBee, ABS), Queensland Institute of Medical Research (AOCS), Brisbane, Australia; Peter MacCallum Cancer Center, Melbourne, Australia (kConFab, AOCS); N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus (NVB, NNA, IVZ); Department of Epidemiology, University of California Irvine, Irvine, CA (HA-C, AZ); Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany (HB, CJ); University of Tübingen, Tübingen, Germany (HB, CJ); Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany (Y-DK); Institute of Pathology, University of Bonn, Bonn, Germany (SHa); University Breast Center (PAF, RS, MWB) and Institute of Human Genetics (ABE), University Hospital Erlangen, Erlangen, Germany; Department of Gynecology and Obstetrics, David Geffen School of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA (PAF); Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia (GGG, GS, LB); Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK (OF, NJ); Cancer Research UK Epidemiology and Genetics Group, London School of Hygiene and Tropical Medicine, London, UK (OF, IdSS, JP); Section of Cancer Genetics (CT, SHi, AR, NR), Institute of Cancer Research (JP), Sutton, Surrey, UK; Department of Clinical Biochemistry and Department of Breast Surgery, Herlev University Hospital, University of Copenhagen, Denmark (BGN, SEB, HF); Seoul National University College of Medicine, Seoul, Korea (DK, K-YY, D-YN); Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Kuopio (AMa, V-MK); Department of Oncology and Department of Pathology, University Hospital of Kuopio and Biocenter Kuopio, Kuopio, Finland (VK); Department of Oncology, Vaasa Central Hospital, Vaasa, Finland (VK); Division of Cancer Epidemiology and Genetics (MG-C, SC) and Hormonal and Reproductive Epidemiology Branch (LAB), National Cancer Institute, Rockville, MD; Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland (JLis); Department of Gynecology and Obstetrics, Ulm Medical School, Ulm, Germany (SW-G); Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (C-YS, H-CW); Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan (J-CY); Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan (S-TC); Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa, Russia (MBe, EK); Department of Medical Genetics, Yakut Research Center of Russian Academy of Medical Sciences, Yakutsk, Russia (TN); Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (MKH, JM, RP, DFE)
Correspondence to: Roger L. Milne, PhD, Genetic and Molecular Epidemiology Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), C/ Melchor Fernández Almagro, 3, 29029, Madrid, Spain (e-mail: rmilne{at}cnio.es).
Background: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.
Methods: 2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.
Results: We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 x 10–19). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P 
.2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10–15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10–14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).
Conclusion: The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.
| CONTEXT AND CAVEATS Prior knowledge 2q35-rs13387042 has been identified as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. Study design Genetic association study of breast cancer risk and rs13387042 using data from 25 case–control studies in the Breast Cancer Association Consortium. Contribution Having the rs13387042 genotype was associated with increased risk of breast cancer among white women of European origin, but the magnitude of the association was lower than that found previously. The association did not vary by age or ethnicity but was stronger among patients with a family history and was observed in ER-positive and -negative and progesterone receptor–positive and –negative disease. Implications The single-nucleotide polymorphism 2q35-rs13387042 is associated with increased risk of ER-positive and -negative breast cancer among white European women in this study. Limitations Hormone receptor status was not available for all patients and available data were taken from medical records rather than being confirmed by pathology review; thus, the statistical power was lower in the analyses for hormone receptor status. From the Editors
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Manuscript received November 28, 2008; revised April 17, 2009; accepted May 13, 2009.
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