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
- Equal contributors
1 Genetic Cancer Susceptibility group, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon 69372, France
2 Genetic of Breast Cancer group, Cancer Research Center of Lyon, Centre Léon Bérard, 28 rue Laennec, Lyon 69008, France
3 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, 2000 Circle of Hope, Salt Lake City, UT 84112, USA
4 University of Texas at Austin, Austin, TX 78712, USA
5 Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA
6 Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC 3010, Australia
7 Genetic Epidemiology Laboratory, The University of Melbourne, 207 Bouverie Street, Melbourne, VIC 3010, Australia
8 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, 600 University Avenue, Toronto, ON M5G 1X5, Canada
9 Cancer Prevention Institute of California, 2201 Walnut Avenue, Fremont, CA 94538, USA
10 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, 2000 Circle of Hope, Salt Lake City, UT 84112, USA
11 Genetic Epidemiology of Cancer team, Inserm, U900, Institut Curie, Mines ParisTech, 26 rue d’Ulm, Paris 75248, France
12 Stanford University School of Medicine and Stanford Cancer Institute, 875 Blake Wilbur Drive, Stanford, CA 94305, USA
13 Department of Epidemiology (Genome Epidemiology Lab), Seoul National University School of Public Health, 599 Gwanak-ro Granak-gu, Seoul 151-742, Korea
Breast Cancer Research 2014, 16:R58 doi:10.1186/bcr3669Published: 3 June 2014
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.
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.