Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls.
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Nick Orr;
Alan Ashworth;
Heli Nevanlinna;
Tuomas Heikkinen;
Kristiina Aittomäki;
Carl Blomqvist;
Barbara Burwinkel;
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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;
John L Hopper;
Fergus J Couch;
Janet E Olson;
Xianshu Wang;
Zachary Fredericksen;
Peter Schürmann;
Regina Waltes;
Michael Bremer;
Thilo Dörk;
Peter Devilee;
Christie J van Asperen;
Rob AEM Tollenaar;
Caroline Seynaeve;
Per Hall;
Kamila Czene;
Keith Humphreys;
Jianjun Liu;
Shahana Ahmed;
Alison M Dunning;
Melanie Maranian;
Paul DP Pharoah;
Georgia Chenevix-Trench;
kConFab Investigators;
AOCS Group;
Jonathan Beesley;
Natalia V Bogdanova;
Natalia N Antonenkova;
Iosif V Zalutsky;
Hoda Anton-Culver;
Argyrios Ziogas;
Hiltrud Brauch;
Yon-Dschun Ko;
Ute Hamann;
GENICA Consortium;
Peter A Fasching;
Reiner Strick;
Arif B Ekici;
Matthias W Beckmann;
Graham G Giles;
Gianluca Severi;
Laura Baglietto;
Dallas R English;
Roger L Milne;
Javier Benítez;
José Ignacio Arias;
Guillermo Pita;
Børge G Nordestgaard;
Stig E Bojesen;
Henrik Flyger;
Daehee Kang;
Keun-Young Yoo;
Dong Young Noh;
Arto Mannermaa;
Vesa Kataja;
Veli-Matti Kosma;
Montserrat García-Closas;
Stephen Chanock;
Jolanta Lissowska;
Louise A Brinton;
Jenny Chang-Claude;
Shan Wang-Gohrke;
Annegien Broeks;
Marjanka K Schmidt;
Flora E van Leeuwen;
Laura J Van't Veer;
Sara Margolin;
Annika Lindblom;
Manjeet K Humphreys;
Jonathan Morrison;
Radka Platte;
Douglas F Easton;
Julian Peto ;
Breast Cancer Association Consortium;
(2010)
Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls.
Cancer epidemiology, biomarkers & prevention, 19 (9).
pp. 2143-2151.
ISSN 1055-9965
DOI: 10.1158/1055-9965.EPI-10-0374
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 familial cases was 1.12 (95% confidence interval, 1.02-1.23; P(trend) = 0.02). CONCLUSIONS: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. IMPACT: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.