Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3) was identified in early DNA damage response gene, MCPH1, significantly associating with breast cancer susceptibility both in familial (5/145, 3.4%, P = 0.003, OR 8.3) and unselected cases (16/1150, 1.4%, P = 0.016, OR 3.3). A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas (P = 0.0007). Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for spontaneous chromosomal rearrangements in peripheral blood lymphocytes (P = 0.0007), suggesting an effect for MCPH1 haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type allele. These findings collectively provide strong evidence for MCHP1 being a novel breast cancer susceptibility gene, which warrants further investigations in other populations.
References
[1]
Turnbull C, Rahman N. Genetic predisposition to breast cancer: Past, present, and future. Annual Review of Genomics and Human Genetics 2008;9:321–345. doi: 10.1146/annurev.genom.9.081307.164339. pmid:18544032
[2]
Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 2002 Aug;71(2):432–438. pmid:12094328 doi: 10.1086/341943
[3]
Erkko H, Xia B, Nikkil？ J, Schleutker J, Syrj？koski K, Mannermaa A, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 2007;446(7133):316–319. pmid:17287723 doi: 10.1038/nature05609
[4]
Rai R, Dai H, Multani AS, Li K, Chin K, Gray J, et al. BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer. Cancer Cell 2006;10(2):145–157. pmid:16872911 doi: 10.1016/j.ccr.2006.07.002
[5]
Wu X, Mondal G, Wang X, Wu J, Yang L, Pankratz VS, et al. Microcephalin regulates BRCA2 and Rad51-associated DNA double-strand break repair. Cancer Res 2009;69(13):5531–5536. doi: 10.1158/0008-5472.CAN-08-4834. pmid:19549900
[6]
Peng G, Yim E-, Dai H, Jackson AP, van der Burgt I, Pan M-, et al. BRIT1/MCPH1 links chromatin remodelling to DNA damage response. Nat Cell Biol 2009;11(7):865–872. doi: 10.1038/ncb1895. pmid:19525936
[7]
Jackson AP, Eastwood H, Bell SM, Adu J, Toomes C, Carr IM, et al. Identification of microcephalin, a protein implicated in determining the size of the human brain. Am J Hum Genet 2002;71(1):136–142. pmid:12046007 doi: 10.1086/341283
[8]
Alderton GK, Galbiati L, Griffith E, Surinya KH, Neitzel H, Jackson AP, et al. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Nat Cell Biol 2006;8(7):725–733. pmid:16783362 doi: 10.1038/ncb1431
[9]
Yu X, Chini CCS, He M, Mer G, Chen J. The BRCT Domain Is a Phospho-Protein Binding Domain. Science 2003;302(5645):639–642. pmid:14576433 doi: 10.1126/science.1088753
[10]
Wood JL, Liang Y, Li K, Chen J. Microcephalin/MCPH1 associates with the condensin II complex to function in homologous recombination repair. J Biol Chem 2008;283(43):29586–29592. doi: 10.1074/jbc.M804080200. pmid:18718915
Custer BS, Koepsell TD, Mueller BA. The association between breast carcinoma and meningioma in women. Cancer 2002 Mar 15;94(6):1626–1635. pmid:11920521 doi: 10.1002/cncr.10410
[13]
Rieske P, Zakrzewska M, Biernat W, Bartkowiak J, Zimmermann A, Liberski PP. Atypical molecular background of glioblastoma and meningioma developed in a patient with Li-Fraumeni syndrome. J Neurooncol 2005 Jan;71(1):27–30. pmid:15719270 doi: 10.1007/s11060-004-9181-3
[14]
Zhang B, Wang E, Dai H, Hu R, Liang Y, Li K, et al. BRIT1 regulates p53 stability and functions as a tumor suppressor in breast cancer. Carcinogenesis 2013;34(10):2271–2280. doi: 10.1093/carcin/bgt190. pmid:23729656
[15]
Heikkinen K, Rapakko K, Karppinen S-, Erkko H, Knuutila S, Lundán T, et al. RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis 2006;27(8):1593–1599. pmid:16474176 doi: 10.1093/carcin/bgi360
[16]
Bonassi S, Hagmar L, Str？mberg U, Huici Montagud A, Tinnerberg H, Forni A, et al. Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. Cancer Res 2000;60(6):1619–1625. pmid:10749131
[17]
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013. pmid:21376230
[18]
Nikkil？ J, Parplys AC, Pylk？s K, Bose M, Huo Y, Borgmann K, et al. Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nat Commun 2013;4. doi: 10.1038/ncomms3578
[19]
Liang Y, Gao H, Lin S-, Goss JA, Du C, Li K. Mcph1/Brit1 deficiency promotes genomic instability and tumor formation in a mouse model. Oncogene 2014. doi: 10.1038/onc.2014.367
[20]
Roy R, Chun J, Powell SN. BRCA1 and BRCA2: Different roles in a common pathway of genome protection. Nature Reviews Cancer 2012;12(1):68–78. doi: 10.1038/nrc3181
[21]
Wistuba II, Behrens C, Virmani AK, Milchgrub S, Syed S, Stephen L, et al. Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer. Cancer Res 1999;59(8):1973–1979. pmid:10213509
[22]
Pribill I, Speiser P, Leary J, Leodolter S, Hacker NF, Friedlander ML, et al. High frequency of allelic imbalance at regions of chromosome arm 8p in ovarian carcinoma. Cancer Genet Cytogenet 2001;129(1):23–29. pmid:11520561 doi: 10.1016/s0165-4608(01)00419-8
[23]
Miller BJ, Wang D, Krahe R, Wright FA. Pooled Analysis of Loss of Heterozygosity in Breast Cancer: A Genome Scan Provides Comparative Evidence for Multiple Tumor Suppressors and Identifies Novel Candidate Regions. Am J Hum Genet 2003;73(4):748–767. pmid:13680524 doi: 10.1086/378522
[24]
Farmer H, McCabe H, Lord CJ, Tutt AHJ, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434(7035):917–921. pmid:15829967 doi: 10.1038/nature03445
[25]
Vehmanen P, Friedman LS, Eerola H, McClure M, Ward B, Sarantaus L, et al. Low proportion of BRCA1 and BRCA2 mutations in Finnish breast cancer families: Evidence for additional susceptibility genes. Hum Mol Genet 1997;6(13):2309–2315. pmid:9361038 doi: 10.1093/hmg/6.13.2309
[26]
Huusko P, Paakkonen K, Launonen V, Poyhonen M, Blanco G, Kauppila A, et al. Evidence of founder mutations in finnish BRCA1 and BRCA2 families [4]. Am J Hum Genet 1998;62(6):1544–1548. pmid:9585608 doi: 10.1086/301880
[27]
Syrj？koski K, Vahteristo P, Eerola H, Tamminen A, Kivinummi K, Sarantaus L, et al. Population-based study of BRCA1 and BRCA2 mutations in 1035 unselected finnish breast cancer patients. J Natl Cancer Inst 2000;92(18):1529–1531. pmid:10995809 doi: 10.1093/jnci/92.18.1529
[28]
Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylk？s K, Roberts J, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med 2014;371(6):497–506. doi: 10.1056/NEJMoa1400382. pmid:25099575
[29]
Richardson J, Shaaban AM, Kamal M, Alisary R, Walker C, Ellis IO, et al. Microcephalin is a new novel prognostic indicator in breast cancer associated with BRCA1 inactivation. Breast Cancer Res Treat 2011;127(3):639–648. doi: 10.1007/s10549-010-1019-4. pmid:20632086
[30]
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6(269). doi: 10.1126/scisignal.2004088
[31]
Rapakko K, Allinen M, Syrj？koski K, Vahteristo P, Huusko P, V？h？kangas K, et al. Germline TP53 alterations in Finnish breast cancer families are rare and occur at corserved mutation-prone sites. Br J Cancer 2001;84(1):116–119. pmid:11139324 doi: 10.1054/bjoc.2000.1530
[32]
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: Tool for the unification of biology. Nat Genet 2000;25(1):25–29. pmid:10802651 doi: 10.1038/75556
[33]
Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, et al. The STRING database in 2011: Functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 2011;39(SUPPL. 1):D561–D568. doi: 10.1093/nar/gkq973
[34]
Sulonen A-, Ellonen P, Almusa H, Lepist？ M, Eldfors S, Hannula S, et al. Comparison of solution-based exome capture methods for next generation sequencing. Genome Biol 2011;12(10). doi: 10.1186/gb-2011-12-9-r94
[35]
Chang X, Wang K. Wannovar: Annotating genetic variants for personal genomes via the web. J Med Genet 2012;49(7):433–436. doi: 10.1136/jmedgenet-2012-100918. pmid:22717648
Pylk？s K, Vuorela M, Otsukka M, Kallioniemi A, Jukkola-Vuorinen A, Winqvist R. Rare copy number variants observed in hereditary breast cancer cases disrupt genes in estrogen signaling and TP53 tumor suppression network. PLoS Genetics 2012;8(6). doi: 10.1371/journal.pgen.1002734
[38]
Tuupanen S, Niittym？ki I, Nousiainen K, Vanharanta S, Mecklin J-, Nuorva K, et al. Allelic imbalance at rs6983267 suggests selection of the risk allele in somatic colorectal tumor evolution. Cancer Res 2008;68(1):14–17. doi: 10.1158/0008-5472.CAN-07-5766. pmid:18172290
