Tavtigian, Sean V. and Oefner, Peter J. and Babikyan, Davit and Hartmann, Anne and Healey, Sue and Le Calvez-Kelm, Florence and Lesueur, Fabienne and Byrnes, Graham B. and Chuang, Shu-Chun and Forey, Nathalie and Feuchtinger, Corinna and Gioia, Lydie and Hall, Janet and Hashibe, Mia and Herte, Barbara and McKay-Chopin, Sandrine and Thomas, Alun and Vallee, Maxime P. and Voegele, Catherine and Webb, Penelope M. and Whiteman, David C. and Sangrajrang, Suleeporn and Hopper, John L. and Southey, Melissa C. and Andrulis, Irene L. and John, Esther M. and Chenevix-Trench, Georgia (2009) Rare, Evolutionarily Unlikely Missense Substitutions in ATM Confer Increased Risk of Breast Cancer. AMERICAN JOURNAL OF HUMAN GENETICS, 85 (4). pp. 427-446. ISSN 0002-9297, 1537-6605
Full text not available from this repository. (Request a copy)Abstract
The susceptibility gene for ataxia telangiectasia, ATM, is also an intermediate-risk breast-cancer-susceptibility gene. However, the spectrum and frequency distribution of ATM mutations that confer increased risk of breast cancer have been controversial. To assess the contribution of rare variants in this gene to risk of breast cancer, we pooled data from seven published ATM case-control mutation-screening studies, including a total of 1544 breast cancer cases and 1224 controls, with data from our own mutation screening of an additional 987 breast cancer cases and 1021 controls. Using an in silico missense-substitution analysis that provides a ranking of missense substitutions from evolutionarily most likely to least likely, we carried out analyses of protein-truncating variants, splice-junction variants, and rare missense variants. We found marginal evidence that the combination of ATM protein-truncating and splice-junction variants contribute to breast cancer risk. There was stronger evidence that a subset of rare, evolutionarily unlikely missense substitutions confer increased risk. On the basis of subset analyses, we hypothesize that rare missense substitutions falling in and around the FAT, kinase, and FATC domains of the protein may be disproportionately responsible for that risk and that a subset of these may confer higher risk than do protein-truncating variants. We conclude that a comparison between the graded distributions of missense substitutions in cases versus controls can complement analyses of truncating variants and help identify susceptibility genes and that this approach will aid interpretation of the data emerging from new sequencing technologies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ATAXIA-TELANGIECTASIA GENE; RESOLUTION MELTING ANALYSIS; AFFECT PROTEIN FUNCTION; EARLY-ONSET; ALLELIC VARIANTS; FAMILIAL BREAST; TRUNCATING MUTATIONS; DNA-DAMAGE; SUSCEPTIBILITY ALLELES; GERMLINE MUTATIONS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Sep 2020 08:32 |
| Last Modified: | 03 Sep 2020 08:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/28279 |
Actions (login required)
 |
View Item |
