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


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.

SUBMITTER: Fletcher O 

PROVIDER: S-EPMC2938473 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Fletcher Olivia O   Johnson Nichola N   dos Santos Silva Isabel I   Orr Nick N   Ashworth Alan A   Nevanlinna Heli H   Heikkinen Tuomas T   Aittomäki Kristiina K   Blomqvist Carl C   Burwinkel Barbara B   Bartram Claus R CR   Meindl Alfons A   Schmutzler Rita K RK   Cox Angela A   Brock Ian I   Elliott Graeme G   Reed Malcolm W R MW   Southey Melissa C MC   Smith Letitia L   Spurdle Amanda B AB   Hopper John L JL   Couch Fergus J FJ   Olson Janet E JE   Wang Xianshu X   Fredericksen Zachary Z   Schürmann Peter P   Waltes Regina R   Bremer Michael M   Dörk Thilo T   Devilee Peter P   van Asperen Christie J CJ   Tollenaar Rob A E M RA   Seynaeve Caroline C   Hall Per P   Czene Kamila K   Humphreys Keith K   Liu Jianjun J   Ahmed Shahana S   Dunning Alison M AM   Maranian Melanie M   Pharoah Paul D P PD   Chenevix-Trench Georgia G   Beesley Jonathan J   Bogdanova Natalia V NV   Antonenkova Natalia N NN   Zalutsky Iosif V IV   Anton-Culver Hoda H   Ziogas Argyrios A   Brauch Hiltrud H   Ko Yon-Dschun YD   Hamann Ute U   Fasching Peter A PA   Strick Reiner R   Ekici Arif B AB   Beckmann Matthias W MW   Giles Graham G GG   Severi Gianluca G   Baglietto Laura L   English Dallas R DR   Milne Roger L RL   Benítez Javier J   Arias José Ignacio JI   Pita Guillermo G   Nordestgaard Børge G BG   Bojesen Stig E SE   Flyger Henrik H   Kang Daehee D   Yoo Keun-Young KY   Noh Dong Young DY   Mannermaa Arto A   Kataja Vesa V   Kosma Veli-Matti VM   García-Closas Montserrat M   Chanock Stephen S   Lissowska Jolanta J   Brinton Louise A LA   Chang-Claude Jenny J   Wang-Gohrke Shan S   Broeks Annegien A   Schmidt Marjanka K MK   van Leeuwen Flora E FE   Van't Veer Laura J LJ   Margolin Sara S   Lindblom Annika A   Humphreys Manjeet K MK   Morrison Jonathan J   Platte Radka R   Easton Douglas F DF   Peto Julian J  

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20100901 9


<h4>Background</h4>Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.<h4>Methods</h4>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.<h4>Results</h4>Combining the data from all five SNP  ...[more]

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