Rare key functional domain missense substitutions in MRE11A, RAD50, and NBNcontribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study

Damiola, Francesca; Pertesi, Maroulio; Oliver, Javier; Le Calvez-Kelm, Florence; Voegele, Catherine; Young, Erin L.; Robinot, Nivonirina; Forey, Nathalie; Durand, Geoffroy; Vallée, Maxime P.; Tao, Kayoko; Roane, Terrell C.; Williams, Gareth J.; Hopper, John L.; Southey, Melissa C.; Andrulis, Irene L.; John, Esther M.; Goldgar, David E.; Lesueur, Fabienne; Tavtigian, Sean V.

doi:10.1186/bcr3669

Title: Rare key functional domain missense substitutions in MRE11A, RAD50, and NBNcontribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study

Journal Article · Tue Jun 03 00:00:00 EDT 2014 · Breast Cancer Research

DOI:https://doi.org/10.1186/bcr3669· OSTI ID:1626700

Damiola, Francesca ^[1]; Pertesi, Maroulio ^[2]; Oliver, Javier ^[2]; Le Calvez-Kelm, Florence ^[2]; Voegele, Catherine ^[2]; Young, Erin L. ^[3]; Robinot, Nivonirina ^[2]; Forey, Nathalie ^[2]; Durand, Geoffroy ^[2]; Vallée, Maxime P. ^[2]; Tao, Kayoko ^[3]; Roane, Terrell C. ^[4]; Williams, Gareth J. ^[5]; Hopper, John L. ^[6]; Southey, Melissa C. ^[7]; Andrulis, Irene L. ^[8]; John, Esther M. ^[9]; Goldgar, David E. ^[3]; Lesueur, Fabienne ^[10]; Tavtigian, Sean V. ^[3]

International Agency for Research on Cancer, Lyon (France); Cancer Research Center of Lyon (France)
International Agency for Research on Cancer, Lyon (France)
University of Utah, Salt Lake City, UT (United States)
University of Texas, Austin, TX (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
University of Melbourne (Australia); Seoul National University (Korea, Republic of)
University of Melbourne (Australia)
University of Toronto, ON (Canada)
Cancer Prevention Institute of California, Fremont, CA (United States); Stanford University, CA (United States)
International Agency for Research on Cancer, Lyon (France); Institute Curie, Paris (France)

The 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? 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). 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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Cancer Institute (NCI); Canadian Institutes of Health Research (CIHR); Canadian Institutes of Health Research

Grant/Contract Number:: AC02-05CH11231; R01 CA121245; UM1CA164920; P30 CA042014

OSTI ID:: 1626700

Journal Information:: Breast Cancer Research, Vol. 16, Issue 3; ISSN 1465-542X

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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sort intolerant from tolerant
Biallelic mutation

Title: Rare key functional domain missense substitutions in MRE11A, RAD50, and NBNcontribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study

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