A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication

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• 作者：Rebecca Hein (1) (2)
  Dieter Flesch-Janys (3)
  Norbert Dahmen (4)
  Lars Beckmann (1) (5)
  Sara Lindstr?m (6) (7) (8)
  Nils Schoof (9)
  Kamila Czene (9)
  Kirstin Mittelstra? (10)
  Thomas Illig (10) (11)
  Petra Seibold (1)
  Sabine Behrens (1)
  Keith Humphreys (9)
  Jingmei Li (12)
  Jianjun Liu (12)
  Janet E. Olson (13)
  Xianshu Wang (13)
  Susan E. Hankinson (7)
  Thérèse Truong (14) (15)
  Florence Menegaux (14) (15)
  Isabel dos Santos Silva (16)
  Nichola Johnson (17)
  Shou-Tung Chen (24)
  Jyh-Cherng Yu (25)
  Argyrios Ziogas (26)
  Vesa Kataja (27) (28)
  Veli-Matti Kosma (29) (30) (31)
  Arto Mannermaa (29) (30) (31)
  Hoda Anton-Culver (32)
  Chen-Yang Shen (33) (34)
  Hiltrud Brauch (18)
  Julian Peto (16)
  Pascal Guénel (14) (15)
  Peter Kraft (6) (7) (8)
  Fergus J. Couch (13)
  Douglas F. Easton (35)
  Per Hall (9)
  Jenny Chang-Claude (1)
  
• 关键词：Postmenopausal breast cancer risk ; Menopausal hormone therapy ; Polymorphisms ; Gene ; environment interaction ; Genome ; wide association study ; Case ; only study
• 刊名：Breast Cancer Research and Treatment
• 出版年：2013
• 出版时间：April 2013
• 年：2013
• 卷：138
• 期：2
• 页码：529-542
• 全文大小：559KB
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• 作者单位：Rebecca Hein (1) (2)
  Dieter Flesch-Janys (3)
  Norbert Dahmen (4)
  Lars Beckmann (1) (5)
  Sara Lindstr?m (6) (7) (8)
  Nils Schoof (9)
  Kamila Czene (9)
  Kirstin Mittelstra? (10)
  Thomas Illig (10) (11)
  Petra Seibold (1)
  Sabine Behrens (1)
  Keith Humphreys (9)
  Jingmei Li (12)
  Jianjun Liu (12)
  Janet E. Olson (13)
  Xianshu Wang (13)
  Susan E. Hankinson (7)
  Thérèse Truong (14) (15)
  Florence Menegaux (14) (15)
  Isabel dos Santos Silva (16)
  Nichola Johnson (17)
  Shou-Tung Chen (24)
  Jyh-Cherng Yu (25)
  Argyrios Ziogas (26)
  Vesa Kataja (27) (28)
  Veli-Matti Kosma (29) (30) (31)
  Arto Mannermaa (29) (30) (31)
  Hoda Anton-Culver (32)
  Chen-Yang Shen (33) (34)
  Hiltrud Brauch (18)
  Julian Peto (16)
  Pascal Guénel (14) (15)
  Peter Kraft (6) (7) (8)
  Fergus J. Couch (13)
  Douglas F. Easton (35)
  Per Hall (9)
  Jenny Chang-Claude (1)
  
  1. Unit of Genetic Epidemiology, Division of Cancer Epidemiology (C020), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg, Germany
  2. PMV Research Group at the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany
  3. Department of Cancer Epidemiology, Clinical Cancer Registry, University Cancer Center and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany
  4. Congenics AG, Hamburg, Germany
  5. Foundation for Quality and Efficiency in Health Care (IQWIG), Cologne, Germany
  6. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA
  7. Department of Epidemiology, Harvard School Of Public Health, Boston, MA, 02138, USA
  8. Department of Biostatistics, Harvard School Of Public Health, Boston, MA, 02138, USA
  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
  10. Research Unit of Molecular Epidemiology, Helmholtz Center Munich, Munich, Germany
  11. Hannover Unified Biobank, Hannover Medical School, Hannover, Germany
  12. Human Genetics, Genome Institute of Singapore, 60 Biopolis St, Singapore, 138672, Singapore
  13. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  14. Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, Villejuif, France
  15. University Paris-Sud, UMRS 1018, Villejuif, France
  16. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK
  17. Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK
  24. Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
  25. Department of Surgery, Tri-Service General Hospital, Taipei, Taiwan
  26. Department of Epidemiology, School of Medicine, University of California, Irvine, CA, USA
  27. School of Medicine, Institute of Clinical Medicine, Oncology, Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
  28. Cancer Center, Kuopio University Hospital, Kuopio, Finland
  29. School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland
  30. Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
  31. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland
  32. Department of Epidemiology, University of California Irvine, Irvine, CA, USA
  33. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
  34. Taiwan Biobank, Taipei, Taiwan
  18. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, University of Tübingen, Tübingen, Germany
  35. Centre for Cancer Genetic Epidemiology, Departments of Public Health and Primary Care and Oncology, University of Cambridge, Cambridge, UK
  
• ISSN：1573-7217

文摘

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6?months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6?×?10? for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P?=?3?×?10?) on chromosome 2 but was not replicated in the BCAC studies (P?=?0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP?×?MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.