Dataset Information

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]

PMID: 20826828

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Project description:BACKGROUND: Individuals heterozygous for germline ATM mutations have been reported to have an increased risk for breast cancer but the role for ATM genetic variants for breast cancer risk has remained unclear. Recently, a common ATM variant, ATMivs38 -8T>C in cis with the ATMex39 5557G>A (D1853N) variant, was suggested to associate with bilateral breast cancer among familial breast cancer patients from Northern Finland. We have here evaluated the 5557G>A and ivs38-8T>C variants in an extensive case-control association analysis. We also aimed to investigate whether there are other ATM mutations or variants contributing to breast cancer risk in our population. METHODS: Two common ATM variants, 5557G>A and ivs38-8T>C, previously suggested to associate with bilateral breast cancer, were genotyped in an extensive set of 786 familial and 884 unselected breast cancer cases as well as 708 healthy controls. We also screened the entire coding region and exon-intron boundaries of the ATM gene in 47 familial breast cancer patients and constructed haplotypes of the patients. The identified variants were also evaluated for increased breast cancer risk among additional breast cancer cases and controls. RESULTS: Neither of the two common variants, 5557G>A and ivs38-8T>C, nor any haplotype containing them, was significantly associated with breast cancer risk, bilateral breast cancer or multiple primary cancers in any of the patient groups or subgoups. Three rare missense alterations and one intronic change were each found in only one patient of over 250 familial patients studied and not among controls. The fourth missense alteration studied further was found with closely similar frequencies in over 600 familial cases and controls. CONCLUSION: Altogether, our results suggest very minor effect, if any, of ATM genetic variants on familial breast cancer in Southern Finland. Our results do not support association of the 5557G>A or ivs38-8T>C variant with increased breast cancer risk or with bilateral breast cancer.

Project description:BackgroundAtaxia telangiectasia mutated (ATM) gene plays a key role in response to DNA lesions and is related to the invasion and metastasis of malignancy. Epidemiological studies have indicated associations between ATM rs1801516 polymorphism and different types of cancer, but their results are inconsistent. To further evaluate the effect of ATM rs1801516 polymorphism on cancer risk, we conducted this meta-analysis.MethodsStudies were identified according to specific inclusion criteria by searching PubMed, Web of Science, and Embase databases. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) under recessive, dominant, codominant, and overdominant models of inheritance were calculated to estimate the association between rs1801516 polymorphism and cancer risk.ResultsA total of 37 studies with 12,879 cases and 18,054 controls were included in our study. No significant association was found between rs1801516 polymorphism and cancer risk in overall comparisons (AA vs GG + GA: OR = 0.91, 95% CI, 0.78-1.07; AA+GA vs GG: OR = 1.00, 95% CI, 0.90-1.11; AA vs GG: OR = 0.89, 95% CI, 0.75-1.06; GA vs GG: OR = 1.01, 95% CI, 0.91-1.13; GG + AA vs GA: OR = 1.00, 95% CI, 0.88-1.10). However, after subgroup analyses by region-specified population, significant associations were found in European (AA vs GG + GA: OR = 0.79, 95% CI, 0.65-0.96, P = 0.017; AA vs GG: OR = 0.79, 95% CI, 0.65-0.96, P = 0.017), South American (AA+GA vs GG: OR = 2.15, 95% CI, 1.37-3.38, P = 0.001; GA vs GG: OR = 2.19, 95% CI, 1.38-3.47, P = 0.001; GG + AA vs GA: OR = 0.46, 95% CI, 0.29-0.72, P = 0.001), and Asian (AA vs GG + GA: OR = 7.45, 95% CI, 1.31-42.46, P = 0.024; AA vs GG: OR = 7.40, 95% CI, 1.30-42.19, P = 0.024). Subgroup analyses also revealed that compared with subjects carrying a GG genotype, those carrying a homozygote AA had a decreased risk for breast cancer (AA vs GG: OR = 0.76, 95% CI, 0.59-0.98, P = 0.035), and the homozygote AA was associated with decreased cancer risk in subjects with family history (AA vs GG: OR = 0.68, 95% CI, 0.47-0.98, P = 0.039).ConclusionsATM rs1801516 polymorphism is not associated with overall cancer risk in total population. However, for subgroup analyses, this polymorphism is especially associated with breast cancer risk; in addition, it is associated with overall cancer risk in Europeans, South Americans, Asians, and those with family history.

Dataset Information

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

Background

Methods

Results

Conclusions

Impact

Publications

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

Similar Datasets

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