Horne HN 1 , Chung CC 1 , Zhang H 1 , Yu K 1 , Prokunina-Olsson L 1 , Michailidou K 2 Show all authors , Bolla MK 2 , Wang Q 2 , Dennis J 2 , Hopper JL 3 , Southey MC 4 , Schmidt MK 5 , Broeks A 5 , Muir K 6 , Lophatananon A 6 , Fasching PA 7 , Beckmann MW 7 , Fletcher O 8 , Johnson N 8 , Sawyer EJ 9 , Tomlinson I 10 , Burwinkel B 11 , Marme F 11 , Guénel P 12 , Truong T 12 , Bojesen SE 13 , Flyger H 14 , Benitez J 15 , González-Neira A 15 , Anton-Culver H 16 , Neuhausen SL 17 , Brenner H 18 , Arndt V 18 , Meindl A 19 , Schmutzler RK 20 , Brauch H 21 , Hamann U 22 , Nevanlinna H 23 , Khan S 23 , Matsuo K 24 , Iwata H 25 , Dörk T 26 , Bogdanova NV 27 , Lindblom A 28 , Margolin S 29 , Mannermaa A 30 , Kosma VM 30 , Chenevix-Trench G 31 , kConFab/AOCS Investigators , Wu AH 32 , Ven den Berg D 32 , Smeets A 33 , Zhao H 34 , Chang-Claude J 35 , Rudolph A 35 , Radice P 36 , Barile M 37 , Couch FJ 38 , Vachon C 39 , Giles GG 3 , Milne RL 3 , Haiman CA 32 , Marchand LL 40 , Goldberg MS 41 , Teo SH 42 , Taib NA 43 , Kristensen V 44 , Borresen-Dale AL 44 , Zheng W 45 , Shrubsole M 45 , Winqvist R 46 , Jukkola-Vuorinen A 47 , Andrulis IL 48 , Knight JA 49 , Devilee P 50 , Seynaeve C 51 , García-Closas M 1 , Czene K 52 , Darabi H 52 , Hollestelle A 51 , Martens JW 51 , Li J 52 , Lu W 53 , Shu XO 45 , Cox A 54 , Cross SS 55 , Blot W 45 , Cai Q 45 , Shah M 56 , Luccarini C 56 , Baynes C 56 , Harrington P 56 , Kang D 57 , Choi JY 58 , Hartman M 59 , Chia KS 59 , Kabisch M 22 , Torres D 22 , Jakubowska A 60 , Lubinski J 60 , Sangrajrang S 61 , Brennan P 62 , Slager S 39 , Yannoukakos D 63 , Shen CY 64 , Hou MF 65 , Swerdlow A 66 , Orr N 8 , Simard J 67 , Hall P 52 , Pharoah PD 2 , Easton DF 2 , Chanock SJ 1 , Dunning AM 56 , Figueroa JD 1

Affiliations 

  • 1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States of America
  • 2 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 3 Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Australia
  • 4 Department of Pathology, The University of Melbourne, Melbourne, Australia
  • 5 Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
  • 6 Division of Health Sciences, Warwick Medical School, Warwick University, Coventry, UK
  • 7 Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany
  • 8 Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
  • 9 Research Oncology, Guy's Hospital, King's College London, London, UK
  • 10 Wellcome Trust Centre for Human Genetics and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
  • 11 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
  • 12 Environmental Epidemiology of Cancer, Center for Research in Epidemiology and Population Health, INSERM, Villejuif, France
  • 13 Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 14 Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
  • 15 Human Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain
  • 16 Department of Epidemiology, University of California Irvine, Irvine, CA, United States of America
  • 17 Beckman Research Institute of City of Hope, Duarte, CA, United States of America
  • 18 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 19 Division of Gynaecology and Obstetrics, Technische Universität München, Munich, Germany
  • 20 Division of Molecular Gyneco-Oncology, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany
  • 21 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 22 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 23 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 24 Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan
  • 25 Department of Breast Oncology, Aichi Cancer Center Hospital, Aichi, Japan
  • 26 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
  • 27 Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
  • 28 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  • 29 Department of Oncology - Pathology, Karolinska Institutet, Stockholm, Sweden
  • 30 Cancer Center, Kuopio University Hospital, Kuopio, Finland
  • 31 Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
  • 32 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States of America
  • 33 University Hospital Gashuisberg, Leuven, Belgium
  • 34 Vesalius Research Center, Leuven, Belgium
  • 35 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 36 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 37 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy
  • 38 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States of America
  • 39 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States of America
  • 40 University of Hawaii Cancer Center, Honolulu, HI, United States of America
  • 41 Department of Medicine, McGill University, Montreal, Canada
  • 42 Cancer Research Initiatives Foundation, Subang Jaya, Selangor, Malaysia
  • 43 Breast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, KualaLumpur, Malaysia
  • 44 Department of Genetics, Institute for Cancer Research, Radiumhospitalet, Oslo University Hospital, Oslo University Hospital, Oslo, Norway
  • 45 Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, United States of America
  • 46 Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu, Finland
  • 47 Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland
  • 48 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada
  • 49 Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada
  • 50 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  • 51 Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 52 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  • 53 Shanghai Center for Disease Control and Prevention, Shanghai, China
  • 54 Sheffield Cancer Research, Department of Oncology, University of Sheffield, Sheffield, UK
  • 55 Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK
  • 56 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
  • 57 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
  • 58 Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea
  • 59 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
  • 60 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 61 National Cancer Institute, Bangkok, Thailand
  • 62 International Agency for Research on Cancer, Lyon, France
  • 63 Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research "Demokritos", Athens, Greece
  • 64 School of Public Health, China Medical University, Taichung, Taiwan
  • 65 Cancer Center and Department of Surgery, Chung-Ho Memorial Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
  • 66 Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
  • 67 Centre Hospitalier Universitaire de Québec Research Center, Laval University, Québec City, Canada
PLoS ONE, 2016;11(8):e0160316.
PMID: 27556229 DOI: 10.1371/journal.pone.0160316

Abstract

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.