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
Francesca Damiola,Maroulio Pertesi,Javier Oliver,Florence Le Calvez-Kelm,Catherine Voegele,Erin L. Young,Nivonirina Robinot,Nathalie Forey,Geoffroy Durand,Maxime Vallée,Kayoko Tao,Terrell C Roane,Gareth J. Williams,John L. Hopper,John L. Hopper,Melissa C. Southey,Irene L. Andrulis,Esther M. John,Esther M. John,David E. Goldgar,Fabienne Lesueur,Fabienne Lesueur,Sean V. Tavtigian +22 more
TLDR
It is established that MRE11A, RAD50, and NBN are intermediate-risk breast cancer susceptibility genes, and like ATM and CHEK2, their spectrum of pathogenic variants includes a relatively high proportion of missense substitutions.Abstract:
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.read more
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Gene-Panel Sequencing and the Prediction of Breast-Cancer Risk
Douglas F. Easton,Paul D.P. Pharoah,Antonis C. Antoniou,Marc Tischkowitz,Sean V. Tavtigian,Katherine L. Nathanson,Peter Devilee,Alfons Meindl,Fergus J. Couch,Melissa C. Southey,David E. Goldgar,D. Gareth Evans,Georgia Chenevix-Trench,Nurul Hidayah Ab Rahman,Mark E. Robson,Susan M. Domchek,William D. Foulkes +16 more
TL;DR: An international group of cancer geneticists review the level of evidence for the association of gene variants with the risk of breast cancer and it is difficult to draw firm conclusions from the data because of ascertainment bias and the lack of data from large populations.
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A Population-Based Study of Genes Previously Implicated in Breast Cancer
Chunling Hu,Steven N. Hart,Rohan Gnanaolivu,Hongyan Huang,Kun Y. Lee,Jie Na,Chi Gao,Jenna Lilyquist,Siddhartha Yadav,Nicholas J. Boddicker,Raed Samara,Josh Klebba,Christine B. Ambrosone,Hoda Anton-Culver,Paul L. Auer,Elisa V. Bandera,Leslie Bernstein,Kimberly A. Bertrand,Elizabeth S. Burnside,Brian D. Carter,Heather Eliassen,Susan M. Gapstur,Mia M. Gaudet,Christopher A. Haiman,James M. Hodge,David J. Hunter,David J. Hunter,Eric J. Jacobs,Esther M. John,Charles Kooperberg,Allison W. Kurian,Loic Le Marchand,Sara Lindstroem,Tricia Lindstrom,Huiyan Ma,Susan L. Neuhausen,Polly A. Newcomb,Katie M. O'Brien,Janet E. Olson,Irene M. Ong,Tuya Pal,Julie R. Palmer,Alpa V. Patel,Sonya Reid,Lynn Rosenberg,Dale P. Sandler,Christopher G. Scott,Rulla M. Tamimi,Jack A. Taylor,Amy Trentham-Dietz,Celine M. Vachon,Clarice R. Weinberg,Song Yao,Argyrios Ziogas,Jeffrey N. Weitzel,David E. Goldgar,Susan M. Domchek,Katherine L. Nathanson,Peter Kraft,Eric C. Polley,Fergus J. Couch +60 more
TL;DR: In this paper, population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and risk assessment.
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Hereditary breast and ovarian cancer: new genes in confined pathways
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Two decades beyond BRCA1/2: Homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy ☆
TL;DR: The BRCA1 and BRCa2 genes within the larger context of homologous recombination deficiency are discussed; the advances in the understanding of hereditary cancer risk and the dramatic shifts that have occurred in the genetic testing landscape since the landmark 2013 Supreme Court ruling invalidating patents on BRC a1 and bRCA2 genetic testing are discussed.
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Beyond BRCA: New hereditary breast cancer susceptibility genes
TL;DR: This review will summarize current data on new findings in breast cancer susceptibility genes, including rare germline mutations in high penetrant genes, such as TP53 and PTEN, and more frequent mutations in moderate penetrate genes,such as CHEK2, ATM and PALB2.
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