Original Article| Volume 208, ISSUE 9, P455-463, September 2015

Protein-truncating variants in moderate-risk breast cancer susceptibility genes: A meta-analysis of high-risk case-control screening studies

      Several “moderate-risk breast cancer susceptibility genes” have been conclusively identified. Pathogenic mutations in these genes are thought to cause a two to fivefold increased risk of breast cancer. In light of the current development and use of multigene panel testing, the authors wanted to systematically obtain robust estimates of the cancer risk associated with loss-of-function mutations within these genes. An electronic search was conducted to identify studies that sequenced the full coding regions of ATM, CHEK2, BRIP1, PALB2, NBS1, and RAD50 in a general and gene-targeted approach. Inclusion was restricted to studies that sequenced the germline DNA in both high-risk cases and geographically matched controls. A meta-analysis was then performed on protein-truncating variants (PTVs) identified in the studies for an association with breast cancer risk. A total of 10,209 publications were identified, of which 64 studies comprising a total of 25,418 cases and 52,322 controls in the 6 interrogated genes were eligible under our selection criteria. The pooled odds ratios for PTVs in the susceptibility genes were at least >2.6. Additionally, mutations in these genes have shown geographic and ethnic variation. This comprehensive study emphasizes the fact that caution should be taken when identifying certain genes as moderate susceptibility with the lack of sufficient data, especially with regard to the NBS1, RAD50, and BRIP1 genes. Further data from case-control sequencing studies, and especially family studies, are warranted.


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        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Hartmann L.
        • Schaid D.
        • Woods J.
        • et al.
        Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer.
        New Engl J Med. 1999; 340: 77-84
        • Kriege M.
        • Brekelmans C.T.M.
        • Boetes C.
        • et al.
        Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition.
        New Eng J Med. 2004; 351: 427-437
        • Hall M.J.
        • Reid J.E.
        • Burbidge L.A.
        • et al.
        BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer.
        Cancer. 2009; 115: 2222-2233
        • Mann G.J.
        • Thorne H.
        • Balleine R.L.
        • et al.
        Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource.
        Breast Cancer Res. 2006; 8: R12
        • Wang F.
        • Fang Q.
        • Ge Z.
        • et al.
        Common BRCA1 and BRCA2 mutations in breast cancer families: a meta-analysis from systematic review.
        Mol Biol Rep. 2012; 39: 2109-2118
        • Berx G.
        • Cleton-Jansen A.M.
        • Nollet F.
        • et al.
        E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers.
        EMBO J. 1995; 14: 6107-6115
        • Hemminki A.
        • Markie D.
        • Tomlinson I.
        • et al.
        A serine/threonine kinase gene defective in Peutz–Jeghers syndrome.
        Nature. 1998; 391: 184-187
        • Malkin D.
        • Li F.P.
        • Strong L.C.
        • et al.
        Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.
        Science. 1990; 250: 1233-1238
        • Zhang B.
        • Beeghly-Fadiel A.
        • Long J.
        • et al.
        Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence.
        Lancet Oncol. 2011; 12: 477-488
        • Peng S.
        • Lü B.
        • Ruan W.
        • et al.
        Genetic polymorphisms and breast cancer risk: evidence from meta-analyses, pooled analyses, and genome-wide association studies.
        Breast Cancer Res Treat. 2011; 127: 309-324
        • Hollestelle A.
        • Wasielewski M.
        • Martens J.W.
        • et al.
        Discovering moderate-risk breast cancer susceptibility genes.
        Curr Opin Genet Dev. 2010; 20: 268-276
        • Meijers-Heijboer H.
        • van den Ouweland A.
        • Klijn J.
        • et al.
        Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations.
        Nat Genet. 2002; 31: 55-59
        • Walsh T.
        • King M.C.
        Ten genes for inherited breast cancer.
        Cancer Cell. 2007; 11: 103-105
        • Renwick A.
        • Thompson D.
        • Seal S.
        • et al.
        ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.
        Nat Genet. 2006; 38: 873-875
        • Vahteristo P.
        • Bartkova J.
        • Eerola H.
        • et al.
        A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer.
        Am J Hum Genet. 2002; 71: 432-438
        • Seal S.
        • Thompson D.
        • Renwick A.
        • et al.
        Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles.
        Nat Genet. 2006; 38: 1239-1241
        • Rahman N.
        • Seal S.
        • Thompson D.
        • et al.
        PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.
        Nat Genet. 2007; 39: 165-167
        • Steffen J.
        • Nowakowska D.
        • Niwińska A.
        • et al.
        Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland.
        Int J Cancer. 2006; 119: 472-475
        • Heikkinen K.
        • Karppinen S.M.
        • Soini Y.
        • et al.
        Mutation screening of Mre11 complex genes: indication of RAD50 involvement in breast and ovarian cancer susceptibility.
        J Med Genet. 2003; 40: e131
        • Turnbull C.
        • Rahman N.
        Genetic predisposition to breast cancer: past, present, and future.
        Annu Rev Genomics Hum Genet. 2008; 9: 321-345
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
        PLoS Med. 2009; 6: e1000100
        • Antoniou A.C.
        • Easton D.F.
        Polygenic inheritance of breast cancer: implications for design of association studies.
        Genet Epidemiol. 2003; 25: 190-202
        • Desmet F.O.
        • Hamroun D.
        • Lalande M.
        • et al.
        Human Splicing Finder: an online bioinformatics tool to predict splicing signals.
        Nucleic Acids Res. 2009; 37: e67
        • Wigginton J.E.
        • Cutler D.J.
        • Abecasis G.R.
        A note on exact tests of Hardy-Weinberg equilibrium.
        Am J Hum Genet. 2005; 76: 887-893
        • González-Hormazábal P.
        • Bravo T.
        • Blanco R.
        • et al.
        Association of common ATM variants with familial breast cancer in a South American population.
        BMC Cancer. 2008; 8: 117
        • Heikkinen K.
        • Rapakko K.
        • Karppinen S.M.
        • et al.
        Association of common ATM polymorphism with bilateral breast cancer.
        Int J Cancer. 2005; 116: 69-72
        • Izatt L.
        • Greenman J.
        • Hodgson S.
        • et al.
        Identification of germline missense mutations and rare allelic variants in the ATM gene in early-onset breast cancer.
        Genes Chromosomes Cancer. 1999; 26: 286-294
        • Antoniou A.C.
        • Casadei S.
        • Heikkinen T.
        • et al.
        Breast-cancer risk in families with mutations in PALB2.
        N Engl J Med. 2014; 371: 497-506
        • CHEK2 Breast Cancer Case-Control Consortium
        CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies.
        Am J Hum Genet. 2004; 74: 1175-1182
        • Weischer M.
        • Bojesen S.E.
        • Ellervik C.
        • et al.
        CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls.
        J Clin Oncol. 2008; 26: 542-548
        • Bogdanova N.
        • Enssen-Dubrowinskaja N.
        • Feshchenko S.
        • et al.
        Association of two mutations in the CHEK2 gene with breast cancer.
        Int J Cancer. 2005; 116: 263-266
        • Novak D.J.
        • Chen L.Q.
        • Ghadirian P.
        • et al.
        Identification of a novel CHEK2 variant and assessment of its contribution to the risk of breast cancer in French Canadian women.
        BMC Cancer. 2008; 8: 239
        • Rashid M.U.
        • Mohammad N.
        • Faisal S.
        • et al.
        Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan.
        BMC Cancer. 2013; 13: 312
        • Desjardins S.
        • Beauparlant J.C.
        • Labrie Y.
        • et al.
        Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer.
        BMC Cancer. 2009; 9: 181
        • He M.
        • Di G.H.
        • Cao A.Y.
        • et al.
        RAD50 and NBS1 are not likely to be susceptibility genes in Chinese non-BRCA1/2 hereditary breast cancer.
        Breast Cancer Res Treat. 2012; 133: 111-116
        • Fu R.
        • Gartlehner G.
        • Grant M.
        • et al.
        Conducting quantitative synthesis when comparing medical interventions: AHRQ and the Effective Health Care Program.
        J Clin Epidemiol. 2011; 64: 1187-1197
        • Solyom S.
        • Aressy B.
        • Pylkas K.
        • et al.
        Breast cancer-associated Abraxas mutation disrupts nuclear localization and DNA damage response functions.
        Sci Transl Med. 2012; 4: 122ra23
        • Adzhubei I.A.
        • Schmidt S.
        • Peshkin L.
        • et al.
        A method and server for predicting damaging missense mutations.
        Nat Methods. 2010; 7: 248-249
        • Sim N.L.
        • Kumar P.
        • Hu J.
        • et al.
        SIFT web server: predicting effects of amino acid substitutions on proteins.
        Nucleic Acids Res. 2012; 40: 452-457
        • Little J.
        • Bradley L.
        • Bray M.S.
        • et al.
        Reporting, appraising, and integrating data on genotype prevalence and gene-disease associations.
        Am J Epidemiol. 2002; 156: 300-310
        • Mathieson I.
        • McVean G.
        Differential confounding of rare and common variants in spatially structured populations.
        Nat Genet. 2012; 44: 243-246
        • Nelson M.R.
        • Wegmann D.
        • Ehm M.G.
        • et al.
        An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people.
        Science. 2012; 337: 100-104
        • Bellosillo B.
        • Tusquets I.
        • Longarón R.
        • et al.
        Absence of CHEK2 mutations in Spanish families with hereditary breast cancer.
        Cancer Genet Cytogenet. 2005; 161: 93-95
        • Chen W.
        • Yurong S.
        • Liansheng N.
        Breast cancer low-penetrance allele 1100delC in the CHEK2 gene: not present in the Chinese familial breast cancer population.
        Adv Ther. 2008; 25: 496-501
        • Panoutsopoulou K.
        • Tachmazidou I.
        • Zeggini E.
        In search of low-frequency and rare variants affecting complex traits.
        Hum Mol Genet. 2013; 22: R16-R21
        • Huusko P.
        • Juo S.H.
        • Gillanders E.
        • et al.
        Genome-wide scanning for linkage in Finnish breast cancer families.
        Eur J Hum Genet. 2004; 12: 98-104
        • Smith P.
        • McGuffog L.
        • Easton D.F.
        • et al.
        A genome wide linkage search for breast cancer susceptibility genes.
        Genes Chromosomes Cancer. 2006; 45: 646-655
        • O'Dushlaine C.T.
        • Morris D.
        • Moskvina V.
        • et al.
        Population structure and genome-wide patterns of variation in Ireland and Britain.
        Eur J Hum Genet. 2010; 18: 1248-1254
        • Hill E.W.
        • Jobling M.
        • Bradley D.G.
        Y-chromosome variation and Irish origins.
        Nature. 2000; 404: 351-352
        • Manolio T.
        • Collins F.S.
        • Cox N.J.
        • et al.
        Finding the missing heritability of complex diseases.
        Nature. 2009; 461: 747-753