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dc.creatorDamiola, Francescaen_US
dc.creatorPertesi, Maroulioen_US
dc.creatorOliver, Javieren_US
dc.creatorLe Calvez-Kelm, Florenceen_US
dc.creatorVoegele, Catherineen_US
dc.creatorYoung, Erin L.en_US
dc.creatorRobinot, Nivonirinaen_US
dc.creatorForey, Nathalieen_US
dc.creatorDurand, Geoffroyen_US
dc.creatorVallee, Maxime P.en_US
dc.creatorTao, Kayokoen_US
dc.creatorRoane, Terrell C.en_US
dc.creatorWilliams, Gareth J.en_US
dc.creatorHopper, John L.en_US
dc.creatorSouthey, Melissa C.en_US
dc.creatorAndrulis, Irene L.en_US
dc.creatorJohn, Esther M.en_US
dc.creatorGoldgar, David E.en_US
dc.creatorLesueur, Fabienneen_US
dc.creatorTavtigian, Sean V.en_US
dc.date.accessioned2016-10-28T19:53:37Z
dc.date.available2016-10-28T19:53:37Z
dc.date.issued2014en_US
dc.identifierdoi:10.15781/T2542JB77
dc.identifier.citationDamiola, Francesca, Maroulio Pertesi, Javier Oliver, Florence Le Calvez-Kelm, Catherine Voegele, Erin L. Young, Nivonirina Robinot et al. "Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study." Breast Cancer Res, Vol. 16, No. 3 (2014): R58.en_US
dc.identifier.issn1465-542Xen_US
dc.identifier.urihttp://hdl.handle.net/2152/43353
dc.description.abstractThe MRE11A-RAD50-Nibrin (MRN) complex plays several critical roles related to repair of DNA double-strand breaks. Inherited mutations in the three components predispose to genetic instability disorders and the MRN genes have been implicated in breast cancer susceptibility, but the underlying data are not entirely convincing. Here, we address two related questions: (1) are some rare MRN variants intermediate-risk breast cancer susceptibility alleles, and if so (2) do the MRN genes follow a BRCA1/BRCA2 pattern wherein most susceptibility alleles are protein-truncating variants, or do they follow an ATM/CHEK2 pattern wherein half or more of the susceptibility alleles are missense substitutions? Methods: Using high-resolution melt curve analysis followed by Sanger sequencing, we mutation screened the coding exons and proximal splice junction regions of the MRN genes in 1,313 early-onset breast cancer cases and 1,123 population controls. Rare variants in the three genes were pooled using bioinformatics methods similar to those previously applied to ATM, BRCA1, BRCA2, and CHEK2, and then assessed by logistic regression. Results: Re-analysis of our ATM, BRCA1, and BRCA2 mutation screening data revealed that these genes do not harbor pathogenic alleles (other than modest-risk SNPs) with minor allele frequencies > 0.1% in Caucasian Americans, African Americans, or East Asians. Limiting our MRN analyses to variants with allele frequencies of < 0.1% and combining protein-truncating variants, likely spliceogenic variants, and key functional domain rare missense substitutions, we found significant evidence that the MRN genes are indeed intermediate-risk breast cancer susceptibility genes (odds ratio (OR) = 2.88, P = 0.0090). Key domain missense substitutions were more frequent than the truncating variants (24 versus 12 observations) and conferred a slightly higher OR (3.07 versus 2.61) with a lower P value (0.029 versus 0.14). Conclusions: These data establish that MRE11A, RAD50, and NBN are intermediate-risk breast cancer susceptibility genes. Like ATM and CHEK2, their spectrum of pathogenic variants includes a relatively high proportion of missense substitutions. However, the data neither establish whether variants in each of the three genes are best evaluated under the same analysis model nor achieve clinically actionable classification of individual variants observed in this study.en_US
dc.description.sponsorshipUnited States National Institutes of Health (NIH) National Cancer Institute (NCI) R01 CA121245en_US
dc.language.isoEnglishen_US
dc.relation.ispartofen_US
dc.rightsAdministrative deposit of works to Texas ScholarWorks: This works author(s) is or was a University faculty member, student or staff member; this article is already available through open access or the publisher allows a PDF version of the article to be freely posted online. The library makes the deposit as a matter of fair use (for scholarly, educational, and research purposes), and to preserve the work and further secure public access to the works of the University.en_US
dc.subjectnijmegen breakage syndromeen_US
dc.subjecttelangiectasia-like disorderen_US
dc.subjectdna-damageen_US
dc.subjectrepairen_US
dc.subjectnbs1en_US
dc.subjectrisken_US
dc.subjectgenesen_US
dc.subjectcomplexen_US
dc.subjectpredispositionen_US
dc.subjectclassificationen_US
dc.subjectoncologyen_US
dc.titleRare Key Functional Domain Missense Substitutions in MRE11A, RAD50, and NBN Contribute to Breast Cancer Susceptibility: Results From a Breast Cancer Family Registry Case-Control Mutation-Screening Studyen_US
dc.typeArticleen_US
dc.description.departmentCenter for Computational Biology and Bioinformaticsen_US
dc.rights.restrictionOpenen_US
dc.identifier.doi10.1186/bcr3669en_US
dc.contributor.utaustinauthorRoane, Terrell C.en_US
dc.relation.ispartofserialBreast Cancer Researchen_US


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