A common coding variant in CASP8 is associated with breast cancer risk

Angela Cox, Alison M. Dunning, Montserrat Garcia-Closas, Sabapathy Balasubramanian, Malcolm W R Reed, Karen A. Pooley, Serena Scollen, Caroline Baynes, Bruce A J Ponder, Stephen Chanock, Jolanta Lissowska, Louise Brinton, Beata Peplonska, Melissa C. Southey, John L. Hopper, Margaret R E McCredie, Graham G. Giles, Olivia Fletcher, Nichola Johnson, Isabel Dos Santos SilvaLorna Gibson, Stig E. Bojesen, Børge G. Nordestgaard, Christen K. Axelsson, Diana Torres, Ute Hamann, Christina Justenhoven, Hiltrud Brauch, Jenny Chang-Claude, Silke Kropp, Angela Risch, Shan Wang-Gohrke, Peter Schürmann, Natalia Bogdanova, Thilo Dörk, Rainer Fagerholm, Kirsimari Aaltonen, Carl Blomqvist, Heli Nevanlinna, Sheila Seal, Anthony Renwick, Michael R. Stratton, Nazneen Rahman, Suleeporn Sangrajrang, David Hughes, Fabrice Odefrey, Paul Brennan, Amanda B. Spurdle, Georgia Chenevix-Trench, Jonathan Beesley, Arto Mannermaa, Jaana Hartikainen, Vesa Kataja, Veli Matti Kosma, Fergus J. Couch, Janet E. Olson, Ellen L. Goode, Annegien Broeks, Marjanka K. Schmidt, Frans B L Hogervorst, Laura J Van t Veer, Daehee Kang, Keun Young Yoo, Dong Young Noh, Sei Hyun Ahn, Sara Wedrén, Per Hall, Yen Ling Low, Jianjun Liu, Roger L. Milne, Gloria Ribas, Anna Gonzalez-Neira, Javier Benitez, Alice J. Sigurdson, Denise L. Stredrick, Bruce H. Alexander, Jeffery P. Struewing, Paul D P Pharoah, Douglas F. Easton

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The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C → A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3′ UTR A → G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P trend = 1.1 × 10-7) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; Ptrend = 2.8 × 10-5). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.

Original languageEnglish (US)
Pages (from-to)352-358
Number of pages7
JournalNature Genetics
Issue number3
StatePublished - Mar 2007

Bibliographical note

Funding Information:
The authors thank all participants for taking part in this research. The Sheffield Breast Cancer Study was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. We thank S. Higham, H. Cramp, D. Connley, I. Brock, G. MacPherson, N. Bhattacharyya and M. Meuth for their contribution to this study. SEARCH was funded by Cancer Research-UK (CR-UK). P.D.P.P. is a Senior Clincal Research Fellow, and D.F.E. is a Principal Research Fellow of CR-UK. The Polish Breast Cancer Study was funded by Intramural Research Funds of the US National Cancer Institute. The authors thank N. Szeszenia-Dabrowska of the Nofer Institute of Occupational Medicine and W. Zatonski of the M.Sklodowska-Curie Institute of Oncology and Cancer Center for their contribution to the Polish Breast Cancer Study. The Australian Breast Cancer Family Study (ABCFS) was funded by the Australian National Health and Medical Research Council (NHMRC), the Victorian Health Promotion Foundation, the New South Wales Cancer Council, and, as part of the Breast Cancer Family Registry, by the US National Cancer Institute (RFA # CA-95-003). The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Cancer Family Registries (CFRs), nor does mention of trade names, commercial products or organizations imply endorsement by the US government or the CFR Centers. The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) is supported by the National Breast Cancer Foundation, the NHMRC of Australia and the Cancer Councils of Queensland, New South Wales, Western Australia, South Australia and Victoria. We thank kConFab nurses; the staff of the Familial Cancer Clinics; H. Thorne, L. Williams, D. Surace, L. Tarcova, E. Niedermayr, S. Picken, H. Holland, G. Dite and X. Chen for their contribution to the ABCFS and kConFab studies; and the Clinical Follow-Up Study of kConFab (funded by the NHMRC grants 145684 and 288704) for supplying some data. The genotyping and analysis were supported by grants from the NHMRC. A.B.S. is funded by an NHMRC Career Development Award, and G.C.-T. and J.L.H. are NHMRC Principal and Senior Principal Research Fellows, respectively. The British Breast Cancer study and the Mammography Oestrogens and Growth Factors study are funded by CR-UK and Breakthrough Breast Cancer. The Copenhagen Breast Cancer Study and The Copenhagen City Heart Study were supported by Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Copenhagen County. The Gene-Environment Interaction and Breast Cancer in Germany (GENICA) study was supported by the German Human Genome Project and funded by the German Federal Ministry of Education and Research (BMBF) (grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114). Genotyping analyses were supported by Deutsches Krebsforschungszentrum, Heidelberg and the Robert Bosch Foundation of Medical Research (Stuttgart). Y. Ko was involved in the design of the GENICA study and was responsible for patient recruitment and collection of clinical data. B. Pesch was involved in the design of the GENICA study and responsible for recruitment of the study subjects as well as collection of epidemiological data. The Genetic Epidemiology Study of Breast Cancer by Age 50 was supported by the Deutsche Krebshilfe e.V. (project number 70492) and the genotyping in part by the state of Baden-Württemberg through the Medical Faculty of the University of Ulm (P.685). We thank U. Eilber, M. Rohrbacher and T. Koehler for their technical support. The Hannover Breast Cancer Study was supported by an intramural grant of Hannover Medical School. N.B. was supported by a fellowship of the German Research Foundation (DO 761/2-1). We acknowledge the technical assistance of M. Haidukiewicz in DNA sample preparation and the initial contributions of P. Yamini to the ARMS assay for the ATM*S49C variant. We thank C. Sohn, A. Scharf, P. Hillemanns, M. Bremer and J. Karstens for their support in terms of infrastructure and patient samples. The Helsinki Breast Cancer Study was supported by The Academy of Finland (project 110663), Helsinki University Central Hospital Research Funds, The Sigrid Juselius Foundation and The Finnish Cancer Society. We thank Research Nurse N. Puolakka for help with the sample and data collection. The Institute of Cancer Research Familial Breast Cancer Study (ICR_FBCS) is supported by Cancer Research UK. The families are recruited by the Breast Cancer Susceptibility Collaboration (UK). The controls are from the British 1958 Birth Cohort DNA collection funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. We thank S. Wiangnon (Khon Kaen University) and P. Boffetta (IARC) for their contributions to the IARC-Thai study and thank V. Gaborieau (IARC) for statistical support for this study. The Kuopio Breast Cancer Project was supported by special Government Funding to Kuopio University Hospital (grant 5654113) and by the Cancer Fund of North Savo. We are grateful to E. Myöhänen for technical assistance. The Mayo Clinic Breast Cancer Study was supported by US National Institutes of Health grants CA82267 and P50 CA116201 and the US medical research and materiel command breast

Funding Information:
cancer IDEA award W81XWH-04-1-0588. ELG is a Fraternal Order of the Eagles Cancer Research Fellow. The Netherlands Cancer Institute thanks L. Braaf, R. Pruntel and R. Tollenaar (Leiden University Medical Center) and other project members of the ‘Clinical outcome of breast cancer in BRCA1/2 carriers’ study, and we are grateful for funding by the Dutch Cancer Society and the Dutch National Genomics Initiative. The Singapore and Swedish Breast Cancer Study (SASBAC) was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. The Seoul Breast Cancer Study was supported by a grant from the National Research and Development Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (0620410-1). The Spanish National Cancer Centre study was supported by the Genome Spain Foundation. We thank E. Gonzalez and C. Alonso for their technical support. The US Radiologic Technologist (USRT) study was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and Center for Cancer Research, National Cancer Institute, US National Institutes of Health. The authors are grateful to the radiologic technologists who participated in the USRT Study; J. Reid of the American Registry of Radiologic Technologists for continued support of this study; D. Kampa and A. Iwan of the University of Minnesota for data collection and study coordination; C. McClure of Research Triangle International for tracing and data management; L. Bowen of Information Management Services for biomedical computing and M. Pineda of the Laboratory of Population Genetics for genotyping assistance.


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