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. 2010 Sep;19(9):2143-51.
doi: 10.1158/1055-9965.EPI-10-0374.

Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls

Olivia Fletcher  1 , Nichola Johnson, Isabel dos Santos Silva, Nick Orr, Alan Ashworth, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Barbara Burwinkel, Claus R Bartram, Alfons Meindl, Rita K Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W R 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 A E M Tollenaar, Caroline Seynaeve, Per Hall, Kamila Czene, Keith Humphreys, Jianjun Liu, Shahana Ahmed, Alison M Dunning, Melanie Maranian, Paul D P 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
Collaborators, Affiliations

Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls

Olivia Fletcher et al. Cancer Epidemiol Biomarkers Prev. 2010 Sep.

Abstract

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.

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Figures

Figure 1
Figure 1
ORs and Ptrends were calculated coding individuals who were common homozygotes for all genotyped SNPs as 0, individuals who were heterozygous for any rare variant as 1 and individuals who were rare homozygotes as 2 (statistical methods). Horizontal lines represent 95% CIs. The diamond represents the combined, fixedeffects estimate of the OR and 95% CI. The vertical line indicates the null effect (OR = 1.0). Trend OR estimates for S49C, S707P, F858L, P1054R and L1420F combined by study in (a) all cases and all controls and (b) bilateral cases and cases with a family history of breast cancer and all controls
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