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

A Corrigendum to this article was published on 01 May 2007

This article has been updated

Abstract

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; Ptrend = 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.

NOTE: In the version of this article initially published, there was an error that affected the calculations of the odds ratios, confidence intervals, between-study heterogeneity, trend test and test for association for SNP ICAM5 V301I in Table 1 (ICAM5 V301I); genotype counts in Supplementary Table 2 (ICAM5; ICR_FBCS and Kuopio studies) and minor allele frequencies, trend test and odds ratios for heterozygotes and rare homozygotes in Supplementary Table 3 (ICAM5; ICR_FBCS and Kuopio studies). The errors in Table 1 have been corrected in the PDF version of the article. The errors in supplementary information have been corrected online.

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Figure 1: Genotype-specific OR and 95% c.i. by study.

Change history

  • 10 April 2007

    NOTE: In the version of this article initially published, there was an error that affected the calculations of the odds ratios, confidence intervals, between-study heterogeneity, trend test and test for association for SNP ICAM5 V301I in Table 1 (ICAM5 V301I); genotype counts in Supplementary Table 2 (ICAM5; ICR_FBCS and Kuopio studies) and minor allele frequencies, trend test and odds ratios for heterozygotes and rare homozygotes in Supplementary Table 3 (ICAM5; ICR_FBCS and Kuopio studies). The errors in Table 1 have been corrected in the PDF version of the article. The errors in supplementary information have been corrected online.

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Acknowledgements

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 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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A.C., A.M.D. and M.G.-C. contributed equally to the writing of this manuscript. Data analysis was carried out by P.D.P.P. and M.G.-C. and the project was coordinated by D.F.E. The Sheffield Breast Cancer Study was designed and initiated by M.W.R.R., and genotyping and data management were coordinated by A.C. S.B. was responsible for patient recruitment, collection and validation of clinicopathological data and assisted in revising the manuscript. The SEARCH study was initiated by B.A.J.P. and is managed by P.D.P.P., D.F.E. and B.A.J.P. Genotyping was coordinated by A.M.D., K.A.P. and C. Baynes carried out genotyping within SEARCH and provided reagents, protocols and technical advice to BCAC members. S. Scollen carried out genotyping and assisted in drafting the manuscript. M.G.-C., L.B., J. Lissowska and B.P. initiated the Polish Breast Cancer Study and participated in the study design as well as in data and biological specimen collection. M.G.-C. was responsible for the overall supervision of the study, quality control, and genotyping. S.C. contributed to genotyping. J.L.H., M.R.E.McC., G.G.G and M.C.S. devised and designed the ABCFS study, were responsible for the recruitment of subjects and collection of samples and critically reviewed the manuscript. A.B.S. participated in the study design, genotyping design, supervision and quality control, data management and critical review of the manuscript for the kConFab study. J. Beesley was involved in genotyping design, implementation, quality control and critical review of the manuscript. G.C.-T. was involved in the study design, funding, project supervision and critical review of manuscript. O.F., N.J., L.G. and I.d.S.S. all participated in the design of the British Breast Cancer Study and collection of the samples. N.J. was responsible for the genotyping and O.F. and L.G. were responsible for coding and cleaning of data. S.E.B., B.G.N. and C.K.A. all initiated the Copenhagen Breast Cancer Study and designed the concept. B.G.N. secured funding and provided administrative support. B.G.N. provided controls, and C.K.A. provided patients. S.E.B. directed the molecular analyses and collected and assembled the data. S.E.B., B.G.N. and C.K.A. all revised the manuscript. U.H. initiated the GENICA study, designed the concept and secured funding. She was responsible for molecular analyses and was involved in revising the manuscript. H.B. initiated and coordinated the GENICA study, designed concepts and secured funding. She is responsible for the conduct of molecular analyses and participated in the revision of the manuscript. C.J. participated in the GENICA study, particularly in the molecular design and analyses, and was involved in revising the manuscript. D.T. participated in the GENICA study, particularly in the molecular design and analyses. J.C.-C. initiated and designed the Genetic Epidemiology Study of Breast Cancer by Age 50, secured funding and participated in revising the manuscript. S.K. was responsible for data collection and analysis and participated in revising the manuscript. A. Risch was responsible for the molecular analyses of IGFBP3 and participated in revising the manuscript. S.W.-G. initiated and conducted the molecular analyses for SOD2 and participated in revising the manuscript. N.B. and P.S. contributed to the molecular design of the Hannover Breast Cancer Study, performed TaqMan assays and ARMS analyses of the HBCS samples and participated in revising the manuscript. T.D. coordinated the Hannover Breast Cancer Study and took part in the project design, experimental work, data evaluation and critical review of the manuscript. R.F. and K.A. coordinated the genotyping, data collection and management, C. Blomquist was responsible for the recruitment of the patients and H.N. initiated and coordinated the Helsinki Breast Cancer Study. M.R.S. and N.R. were responsible for the design of the ICR_FBCS study. S. Seal and A. Renwick undertook the genotyping. The IARC-Thai study was jointly designed by S. Sangrajrang and P.B. S. Sangrajrang coordinated the recruitment of participants and collection of biological samples. The genotyping was coordinated by D.H. and F.O. A.M., V.K. and V.-M.K. participated in the study design for the Kuopio Breast Cancer Project. V.K. coordinated the data collection and clinical data update and contributed to the funding. V.-M.K. was responsible for the histological analyses, revised the manuscript and contributed to the funding. A.M. was responsible for the molecular analyses and was involved in the revision of the manuscript. J.H. contributed to the genotyping and participated in the revision of the manuscript. F.J.C. participated in the Mayo Clinic Breast Cancer Study design, was responsible for the genotyping and was involved in revising the manuscript. J.E.O. oversaw biological sample and data collection and assisted in revising the manuscript, E.L.G. assisted in manuscript revision. A.B., M.K.S., F. B.L.H. and L.J.V.V. were responsible for and/or contributed to project initiation and data collection, performance and interpretation of SNP array test and data cleaning and formatting for Dutch patients (contribution of the Netherlands Cancer Institute) and were involved in revision of the manuscript. P.H., S.W., Y.-L.L. and J. Liu contributed in the securing of funding, study design, genotyping and revision of the manuscript for the SASBAC study. D.K. designed the Seoul Breast Cancer Study. K.-Y.Y. participated in risk factor analysis. D.-Y.N. and S.-H.A. provided biological samples. R.L.M. participated in the CNIO study design, was responsible for data cleaning and formatting and participated in revising the manuscript. G.R. and A.G.-N. were responsible for genotyping and participated in the revision of the manuscript. J. Benitez was responsible for the design of the CNIO study and the securing of funding (Genome Spain grant) and was involved in revising the manuscript. A.J.S. participated in the US Radiologic Technologist (USRT) study design, oversaw biologic sample and data collection and assisted in revising the manuscript. D.L.S. performed the genotyping and participated in the revision of the manuscript. B.H.A. participated in USRT study design, oversaw sample and data collection and assisted in revising the manuscript. J.P.S. participated in the USRT study design, was responsible for the genotyping and was involved in revising the manuscript.

Corresponding author

Correspondence to Angela Cox.

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Supplementary information

Supplementary Fig. 1

Genotype-specific OR and 95% c.i. by study for seven polymorphisms. (PDF 105 kb)

Supplementary Table 1

Characteristics of 20 study samples within the Breast Cancer Association Consortium (BCAC). (PDF 184 kb)

Supplementary Table 2

Genotype counts among cases and controls by study. (PDF 107 kb)

Supplementary Table 3

Association between nine polymorphisms and breast cancer risk by study. (PDF 117 kb)

Supplementary Table 4

Association between nine polymorphisms and breast cancer risk by progesterone receptor status. (PDF 64 kb)

Supplementary Table 5

Association between nine polymorphisms and breast cancer risk by estrogen receptor status. (PDF 65 kb)

Supplementary Table 6

Association between nine polymorphisms and breast cancer risk by age. (PDF 81 kb)

Supplementary Table 7

Association between nine polymorphisms and risk of ductal carcinoma in situ. (PDF 65 kb)

Supplementary Table 8

TaqMan probes and primers. (PDF 42 kb)

Supplementary Table 9

Genotyping quality controls by SNP. (PDF 35 kb)

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Cox, A., Dunning, A., Garcia-Closas, M. et al. A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39, 352–358 (2007). https://doi.org/10.1038/ng1981

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