Journal article

Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls

Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Nick Orr, Alan Ashworth, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomaki, Carl Blomqvist, Barbara Burwinkel, Claus R Bartram, Alfons Meindl, Rita K Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm WR Reed, Melissa C Southey, Letitia Smith, Amanda B Spurdle Show all



BACKGROUND: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. METHODS: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. RESULTS: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (P(trend) = 0.04). The trend OR among bilateral and ..

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Awarded by Academy of Finland

Awarded by Deutsche Krebshilfe

Awarded by National Health and Medical Research Council of Australia (NHMRC)

Awarded by NIH

Awarded by National Cancer Institute, NIH

Awarded by Cancer Care Ontario

Awarded by Columbia University

Awarded by Fox Chase Cancer Center

Awarded by Huntsman Cancer Institute

Awarded by Northern California Cancer Center

Awarded by University of Melbourn

Awarded by German Research Foundation (DFG)

Awarded by Dutch Cancer Society

Awarded by U.S. Army

Awarded by Lon V Smith Foundation

Awarded by German Federal Ministry of Education and Research (BMBF)

Awarded by Fondo de Investigacion Sanitario

Awarded by National Research and Development (R&D) Program for Cancer Control

Awarded by Ministry of Health and Welfare, Republic of Korea

Awarded by Deutsche Krebshilfe e.V.

Awarded by European Union

Awarded by Cancer Research UK (CR-UK)

Awarded by Cancer Research UK

Awarded by The Francis Crick Institute


Funding Acknowledgements

The BBCS is funded by Cancer Research UK (CR-UK) and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre and the National Cancer Research Network. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland grant 110663, the Finnish Cancer Society, and the Sigrid Juselius Foundation. The GC-HBOC study was supported by Deutsche Krebshilfe grant 107054, the Center of Molecular Medicine, Cologne, the Helmholtz Society, and the Dietmar-Hopp Foundation. The SBCS was supported by Yorkshire Cancer Research and the Breast Cancer Campaign. The ABCFS was supported by National Health and Medical Research Council of Australia (NHMRC) grant 145604, NIH grant CA102740-01A2, and National Cancer Institute, NIH grant CA-95-011 through cooperative agreements with members of the Breast Cancer Family Registry and principal investigators, Cancer Care Ontario grant CA69467, Columbia University grant CA69398, Fox Chase Cancer Center grant CA69631, Huntsman Cancer Institute grant CA69446, Northern California Cancer Center grant CA69417, and University of Melbourne grant CA69638. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of collaborating centers in the Breast CFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the Breast CFR. The ABCFS was initially supported by the NHMRC, the New South Wales Cancer Council, and the Victorian Health Promotion Foundation. J.L. Hopper is an Australia Fellow of the NHMRC and Victorian Breast Cancer Research Consortium Group Leader. M. C. Southey and A. B. Spurdle are Senior Research Fellows of the NHMRC. Genotyping was in part supported by the Prostate Cancer Foundation of Australia. The MCBCS was supported by NIH grants CA122340 and CA128978, an NIH Breast Cancer Specialized Program of Research Excellence award to the Mayo Clinic (CA116201), and a Susan G. Komen Breast Cancer Foundation award. The HABCS was supported by an intramural grant from Hannover Medical School and German Research Foundation (DFG) grant Do761/2-1. The HMBCS was supported by short-term fellowships from the German Academic Exchange Program (N. Bogdanova) and the Friends of Hannover Medical School (N. Bogdanova). The ORIGO study was supported by the Dutch Cancer Society. The SASBAC study was supported by the Agency for Science, Technology and Research of Singapore (A*STAR), the NIH, and the Susan G. Komen Breast Cancer Foundation. SEARCH is funded by CR-UK programme grant C490/A11021. A. M. Dunning is supported by CR-UK grant C8197/A10865 and P. D. P. Pharoah is a Senior Clinical Research Fellow of CR-UK. kConFab is supported by grants from the National Breast Cancer Foundation, the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. The kConFab Clinical Follow-Up Study was funded by NHMRC grants 145684, 288704, and 454508. Financial support for the AOCS was provided by U.S. Army Medical Research and Materiel Command grant DAMD17-01-1-0729, the Cancer Council of Tasmania, Cancer Foundation of Western Australia, and NHMRC grant 199600. G. Chenevix-Trench is supported by the NHMRC. The UCIBCS is supported by NIH, National Cancer Institute grant CA-58860 and Lon V Smith Foundation grant LVS-18840.The GENICA study was supported by the German Human Genome Project and German Federal Ministry of Educaton and Research (BMBF) grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114. Genotyping analysis was supported by the Robert Bosch Foundation of Medical Research, Stuttgart, Germany, and the Deutsches Krebsforschungszentrum, Heidelberg, Germany. The work of the BBCC was partly funded by ELAN-Fond of the University Hospital of Erlangen. Infrastructure support for the MCCS recruitment and follow-up is provided by The Cancer Council Victoria, whereas cohort recruitment was partly funded by VicHealth. This work using the MCCS was supported by NHMRC grants 209057, 251533, and 396414 and genotyping was in part supported by the Prostate Cancer Foundation of Australia. The CNIO-BCS was supported by the Genome Spain Foundation, the Red Tematica de Investigacion Cooperativa en Cancer, the Asociacion Espanola Contra Cancer, and Fondo de Investigacion Sanitario grants PI081120 (J. Beesley) and PI081583 (R.L. Milne.). The CGPS was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council, and Copenhagen University Hospital, Herlev Hospital. The SEBCS was supported National Research and Development (R&D) Program for Cancer Control grant 0620410-1 and Korea Health 21 R&D Project grant AO30001, Ministry of Health and Welfare, Republic of Korea. The KBCP is supported by the EVO funds of Kuopio University Hospital and the Finnish Cancer Foundation. The PBCS was funded by Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services. The GESBC was supported by Deutsche Krebshilfe e.V. grant 70492. Funding for the ABCS was provided by Dutch Cancer Society grants NKI 2001-2423 and 2007-3839 and the Dutch National Genomics Initiative. KARBAC acknowledges funding from the Swedish Cancer Society and the Gustav V Julilee Foundation. The BCAC is funded by CR-UK grants C1287/A10118 and C1287/A7497. Meetings of the BCAC have been funded by the European Union COST Programme (BM0606). D. F. Easton is a Principal Research Fellow of CR-UK.