Skip to main content

Advertisement

SpringerLink
Log in

The complex genetic landscape of familial breast cancer

  • Review Paper
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Familial breast cancer represents a minor percentage of all human breast cancers. Mutations in two high susceptibility genes BRCA1 and BRCA2 explain around 25 % of familial breast cancers, while other high, moderate and low susceptibility genes explain up to 20 % more of breast cancer families. Thus, it is important to decipher the genetic architecture of families that show no mutations to improve genetic counselling. The comprehensive description of familial breast cancer using different techniques and platforms has shown to be very valuable for better patient diagnosis, tumour surveillance, and ultimately patient treatment. This review focuses on the complex landscape of pathological, protein, genetic and genomic features associated with BRCA1-, BRCA2-, and non-BRCA1/BRCA2-related cancers described up to date. Special emphasis deserves the coexistence of distinct molecular breast cancer subtypes, the development of tumour classifiers to predict BRCA1/2 mutations, and the last insights from recent whole genome sequencing studies and miRNA profiling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

aCGH:

Array-based comparative genomic hybridisation

BC:

Breast cancer

cCGH:

Conventional or chromosomal-based comparative genomic hybridisation

DSB:

Double strand break DNA

ER:

Oestrogen receptor

FBC:

Familial breast cancer

GAP:

Genomic aberration pattern

GEP:

Gene expression profile

HR:

Homologous recombination DNA repair

IHC:

Immunohistochemistry or immunohistochemical

MLPA:

Multiplex ligation-dependent probe amplification

NGS:

Next generation sequencing

NHEJ:

Non-homologous end joining DNA repair

PR:

Progesterone receptor

SBC:

Sporadic breast cancer

TNBL:

Triple-negative basal-like breast cancers

References

  • Alvarez S, Diaz-Uriarte R, Osorio A, Barroso A, Melchor L, Paz MF, Honrado E, Rodriguez R, Urioste M, Valle L, Diez O, Cigudosa JC, Dopazo J, Esteller M, Benitez J (2005) A predictor based on the somatic genomic changes of the BRCA1/BRCA2 breast cancer tumors identifies the non-BRCA1/BRCA2 tumors with BRCA1 promoter hypermethylation. Clin Cancer Res 11(3):1146–1153

    PubMed  CAS  Google Scholar 

  • Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B, Tulinius H, Thorlacius S, Eerola H, Nevanlinna H, Syrjakoski K, Kallioniemi OP, Thompson D, Evans C, Peto J, Lalloo F, Evans DG, Easton DF (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130. doi:10.1086/375033

    PubMed  CAS  Google Scholar 

  • Arnold JM, Choong DY, Thompson ER, Waddell N, Lindeman GJ, Visvader JE, Campbell IG, Chenevix-Trench G (2010) Frequent somatic mutations of GATA3 in non-BRCA1/BRCA2 familial breast tumors, but not in BRCA1-, BRCA2- or sporadic breast tumors. Breast Cancer Res Treat 119(2):491–496. doi:10.1007/s10549-008-0269-x

    PubMed  CAS  Google Scholar 

  • Badie S, Escandell JM, Bouwman P, Carlos AR, Thanasoula M, Gallardo MM, Suram A, Jaco I, Benitez J, Herbig U, Blasco MA, Jonkers J, Tarsounas M (2010) BRCA2 acts as a RAD51 loader to facilitate telomere replication and capping. Nat Struct Mol Biol 17(12):1461–1469. doi:10.1038/nsmb.1943nsmb.1943

    PubMed  CAS  Google Scholar 

  • Ballal RD, Saha T, Fan S, Haddad BR, Rosen EM (2009) BRCA1 localization to the telomere and its loss from the telomere in response to DNA damage. J Biol Chem 284(52):36083–36098. doi:10.1074/jbc.M109.025825

    PubMed  CAS  Google Scholar 

  • Balleine RL, Provan PJ, Pupo GM, Pathmanathan N, Cummings M, Farshid G, Salisbury EL, Bilous AM, Byth K, Mann GJ (2010) Familial concordance of breast cancer pathology as an indicator of genotype in multiple-case families. Genes Chromosom Cancer 49(12):1082–1094. doi:10.1002/gcc.20816

    PubMed  CAS  Google Scholar 

  • Bane AL, Pinnaduwage D, Colby S, Reedijk M, Egan SE, Bull SB, O’Malley FP, Andrulis IL (2009) Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors. Breast Cancer Res Treat 117(1):183–191. doi:10.1007/s10549-008-0087-1

    PubMed  CAS  Google Scholar 

  • Beger C, Pierce LN, Kruger M, Marcusson EG, Robbins JM, Welcsh P, Welch PJ, Welte K, King MC, Barber JR, Wong-Staal F (2001) Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. Proc Natl Acad Sci USA 98(1):130–135. doi:10.1073/pnas.98.1.13098/1/130

    PubMed  CAS  Google Scholar 

  • Bergamaschi A, Kim YH, Wang P, Sorlie T, Hernandez-Boussard T, Lonning PE, Tibshirani R, Borresen-Dale AL, Pollack JR (2006) Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer 45(11):1033–1040. doi:10.1002/gcc.20366

    PubMed  CAS  Google Scholar 

  • Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning MJ, Barbosa-Morais NL, Teschendorff AE, Green AR, Ellis IO, Tavare S, Caldas C, Miska EA (2007) MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol 8(10):R214. doi:10.1186/gb-2007-8-10-r214

    PubMed  Google Scholar 

  • Borresen AL, Andersen TI, Garber J, Barbier-Piraux N, Thorlacius S, Eyfjord J, Ottestad L, Smith-Sorensen B, Hovig E, Malkin D et al (1992) Screening for germ line TP53 mutations in breast cancer patients. Cancer Res 52(11):3234–3236

    PubMed  CAS  Google Scholar 

  • Bransteitter R, Prochnow C, Chen XS (2009) The current structural and functional understanding of APOBEC deaminases. Cell Mol Life Sci 66(19):3137–3147. doi:10.1007/s00018-009-0070-y

    PubMed  CAS  Google Scholar 

  • Chang S, Wang RH, Akagi K, Kim KA, Martin BK, Cavallone L, Haines DC, Basik M, Mai P, Poggi E, Isaacs C, Looi LM, Mun KS, Greene MH, Byers SW, Teo SH, Deng CX, Sharan SK (2011) Tumor suppressor BRCA1 epigenetically controls oncogenic microRNA-155. Nat Med 17(10):1275–1282. doi:10.1038/nm.2459nm.2459

    PubMed  CAS  Google Scholar 

  • Chen J, Lindblom P, Lindblom A (1998) A study of the PTEN/MMAC1 gene in 136 breast cancer families. Hum Genet 102(1):124–125

    PubMed  CAS  Google Scholar 

  • Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T, Chen F, Feiler H, Tokuyasu T, Kingsley C, Dairkee S, Meng Z, Chew K, Pinkel D, Jain A, Ljung BM, Esserman L, Albertson DG, Waldman FM, Gray JW (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10(6):529–541. doi:10.1016/j.ccr.2006.10.009

    PubMed  CAS  Google Scholar 

  • Comprehensive molecular portraits of human breast tumours (2012) Nature 490 (7418):61–70. doi:10.1038/nature11412

  • Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, Scollen S, Baynes C, Ponder BA, Chanock S, Lissowska J, Brinton L, Peplonska B, Southey MC, Hopper JL, McCredie MR, Giles GG, Fletcher O, Johnson N, dos Santos Silva I, Gibson L, Bojesen SE, Nordestgaard BG, Axelsson CK, Torres D, Hamann U, Justenhoven C, Brauch H, Chang-Claude J, Kropp S, Risch A, Wang-Gohrke S, Schurmann P, Bogdanova N, Dork T, Fagerholm R, Aaltonen K, Blomqvist C, Nevanlinna H, Seal S, Renwick A, Stratton MR, Rahman N, Sangrajrang S, Hughes D, Odefrey F, Brennan P, Spurdle AB, Chenevix-Trench G, Beesley J, Mannermaa A, Hartikainen J, Kataja V, Kosma VM, Couch FJ, Olson JE, Goode EL, Broeks A, Schmidt MK, Hogervorst FB, Van’t Veer LJ, Kang D, Yoo KY, Noh DY, Ahn SH, Wedren S, Hall P, Low YL, Liu J, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Sigurdson AJ, Stredrick DL, Alexander BH, Struewing JP, Pharoah PD, Easton DF (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39(3):352–358. doi:10.1038/ng1981

    PubMed  CAS  Google Scholar 

  • Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, Graf S, Ha G, Haffari G, Bashashati A, Russell R, McKinney S, Langerod A, Green A, Provenzano E, Wishart G, Pinder S, Watson P, Markowetz F, Murphy L, Ellis I, Purushotham A, Borresen-Dale AL, Brenton JD, Tavare S, Caldas C, Aparicio S (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403):346–352. doi:10.1038/nature10983

    PubMed  CAS  Google Scholar 

  • Didraga MA, van Beers EH, Joosse SA, Brandwijk KI, Oldenburg RA, Wessels LF, Hogervorst FB, Ligtenberg MJ, Hoogerbrugge N, Verhoef S, Devilee P, Nederlof PM (2011) A non-BRCA1/2 hereditary breast cancer sub-group defined by aCGH profiling of genetically related patients. Breast Cancer Res Treat 130(2):425–436. doi:10.1007/s10549-011-1357-x

    PubMed  CAS  Google Scholar 

  • Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S, Healey CS, Bowman R, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le Marchand L, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY, Wu PE, Wang HC, Eccles D, Evans DG, Peto J, Fletcher O, Johnson N, Seal S, Stratton MR, Rahman N, Chenevix-Trench G, Bojesen SE, Nordestgaard BG, Axelsson CK, Garcia-Closas M, Brinton L, Chanock S, Lissowska J, Peplonska B, Nevanlinna H, Fagerholm R, Eerola H, Kang D, Yoo KY, Noh DY, Ahn SH, Hunter DJ, Hankinson SE, Cox DG, Hall P, Wedren S, Liu J, Low YL, Bogdanova N, Schurmann P, Dork T, Tollenaar RA, Jacobi CE, Devilee P, Klijn JG, Sigurdson AJ, Doody MM, Alexander BH, Zhang J, Cox A, Brock IW, MacPherson G, Reed MW, Couch FJ, Goode EL, Olson JE, Meijers-Heijboer H, van den Ouweland A, Uitterlinden A, Rivadeneira F, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Hopper JL, McCredie M, Southey M, Giles GG, Schroen C, Justenhoven C, Brauch H, Hamann U, Ko YD, Spurdle AB, Beesley J, Chen X, Mannermaa A, Kosma VM, Kataja V, Hartikainen J, Day NE, Cox DR, Ponder BA (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093. doi:10.1038/nature05887

    PubMed  CAS  Google Scholar 

  • Eisinger F, Nogues C, Guinebretiere JM, Peyrat JP, Bardou VJ, Noguchi T, Vennin P, Sauvan R, Lidereau R, Birnbaum D, Jacquemier J, Sobol H (1999) Novel indications for BRCA1 screening using individual clinical and morphological features. Int J Cancer 84(3):263–267. doi:10.1002/(SICI)1097-0215(19990621)84:3<263:AID-IJC11>3.0.CO;2-G

    PubMed  CAS  Google Scholar 

  • Evans DG, Birch JM, Thorneycroft M, McGown G, Lalloo F, Varley JM (2002) Low rate of TP53 germline mutations in breast cancer/sarcoma families not fulfilling classical criteria for Li-Fraumeni syndrome. J Med Genet 39(12):941–944

    PubMed  CAS  Google Scholar 

  • Farshid G, Balleine RL, Cummings M, Waring P (2006) Morphology of breast cancer as a means of triage of patients for BRCA1 genetic testing. Am J Surg Pathol 30(11):1357–1366. doi:10.1097/01.pas.0000213273.22844.1a

    PubMed  Google Scholar 

  • Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) GLOBOCAN 2008 v1.2., Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. http://globocan.iarc.fr. Accessed May 2011

  • Fernandez-Ramires R, Sole X, De Cecco L, Llort G, Cazorla A, Bonifaci N, Garcia MJ, Caldes T, Blanco I, Gariboldi M, Pierotti MA, Pujana MA, Benitez J, Osorio A (2009) Gene expression profiling integrated into network modelling reveals heterogeneity in the mechanisms of BRCA1 tumorigenesis. Br J Cancer 101(8):1469–1480. doi:10.1038/sj.bjc.6605275

    PubMed  CAS  Google Scholar 

  • Fernandez-Ramires R, Gomez G, Munoz-Repeto I, de Cecco L, Llort G, Cazorla A, Blanco I, Gariboldi M, Pierotti MA, Benitez J, Osorio A (2011) Transcriptional characteristics of familial non-BRCA1/BRCA2 breast tumors. Int J Cancer 128(11):2635–2644. doi:10.1002/ijc.25603

    PubMed  CAS  Google Scholar 

  • Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR, Wong N, Trudel M, Akslen LA (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95(19):1482–1485

    PubMed  CAS  Google Scholar 

  • Foulkes WD, Brunet JS, Stefansson IM, Straume O, Chappuis PO, Begin LR, Hamel N, Goffin JR, Wong N, Trudel M, Kapusta L, Porter P, Akslen LA (2004) The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res 64(3):830–835

    PubMed  CAS  Google Scholar 

  • Fridlyand J, Snijders AM, Ylstra B, Li H, Olshen A, Segraves R, Dairkee S, Tokuyasu T, Ljung BM, Jain AN, McLennan J, Ziegler J, Chin K, Devries S, Feiler H, Gray JW, Waldman F, Pinkel D, Albertson DG (2006) Breast tumor copy number aberration phenotypes and genomic instability. BMC Cancer 6:96. doi:10.1186/1471-2407-6-96

    PubMed  Google Scholar 

  • Gracia-Aznarez FJ, Fernandez V, Pita G, Peterlongo P, Dominguez O, de la Hoya M, Duran M, Osorio A, Moreno L, Gonzalez-Neira A, Rosa-Rosa JM, Sinilnikova O, Mazoyer S, Hopper J, Lazaro C, Southey M, Odefrey F, Manoukian S, Catucci I, Caldes T, Lynch HT, Hilbers FS, van Asperen CJ, Vasen HF, Goldgar D, Radice P, Devilee P, Benitez J (2013) Whole exome sequencing suggests much of non-BRCA1/BRCA2 familial breast cancer is due to moderate and low penetrance susceptibility alleles. PLoS ONE 8(2):e55681. doi:10.1371/journal.pone.0055681

    PubMed  CAS  Google Scholar 

  • Gronwald J, Jauch A, Cybulski C, Schoell B, Bohm-Steuer B, Lener M, Grabowska E, Gorski B, Jakubowska A, Domagala W, Chosia M, Scott RJ, Lubinski J (2005) Comparison of genomic abnormalities between BRCAX and sporadic breast cancers studied by comparative genomic hybridization. Int J Cancer 114(2):230–236. doi:10.1002/ijc.20723

    PubMed  CAS  Google Scholar 

  • Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C, Meltzer PS (2001) Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res 61(16):5979–5984

    PubMed  CAS  Google Scholar 

  • Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, Wilfond B, Borg A, Trent J, Raffeld M, Yakhini Z, Ben-Dor A, Dougherty E, Kononen J, Bubendorf L, Fehrle W, Pittaluga S, Gruvberger S, Loman N, Johannsson O, Olsson H, Sauter G (2001) Gene-expression profiles in hereditary breast cancer. N Engl J Med 344(8):539–548. doi:10.1056/NEJM200102223440801

    PubMed  CAS  Google Scholar 

  • Hedenfalk I, Ringner M, Ben-Dor A, Yakhini Z, Chen Y, Chebil G, Ach R, Loman N, Olsson H, Meltzer P, Borg A, Trent J (2003) Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc Natl Acad Sci USA 100(5):2532–2537. doi:10.1073/pnas.05338051000

    PubMed  CAS  Google Scholar 

  • Heikkinen K, Rapakko K, Karppinen SM, Erkko H, Knuutila S, Lundan T, Mannermaa A, Borresen-Dale AL, Borg A, Barkardottir RB, Petrini J, Winqvist R (2006) RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis 27(8):1593–1599. doi:10.1093/carcin/bgi360

    PubMed  CAS  Google Scholar 

  • Hicks J, Krasnitz A, Lakshmi B, Navin NE, Riggs M, Leibu E, Esposito D, Alexander J, Troge J, Grubor V, Yoon S, Wigler M, Ye K, Borresen-Dale AL, Naume B, Schlicting E, Norton L, Hagerstrom T, Skoog L, Auer G, Maner S, Lundin P, Zetterberg A (2006) Novel patterns of genome rearrangement and their association with survival in breast cancer. Genome Res 16(12):1465–1479. doi:10.1101/gr.5460106

    PubMed  CAS  Google Scholar 

  • Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J (2009) High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res 69(8):3625–3633. doi:10.1158/0008-5472.CAN-08-3426

    PubMed  CAS  Google Scholar 

  • Honrado E, Osorio A, Palacios J, Milne RL, Sanchez L, Diez O, Cazorla A, Syrjakoski K, Huntsman D, Heikkila P, Lerma E, Kallioniemi A, Rivas C, Foulkes WD, Nevanlinna H, Benitez J (2005) Immunohistochemical expression of DNA repair proteins in familial breast cancer differentiate BRCA2-associated tumors. J Clin Oncol 23(30):7503–7511. doi:10.1200/JCO.2005.01.3698

    PubMed  CAS  Google Scholar 

  • Honrado E, Osorio A, Milne RL, Paz MF, Melchor L, Cascon A, Urioste M, Cazorla A, Diez O, Lerma E, Esteller M, Palacios J, Benitez J (2007) Immunohistochemical classification of non-BRCA1/2 tumors identifies different groups that demonstrate the heterogeneity of BRCAX families. Mod Pathol 20(12):1298–1306. doi:10.1038/modpathol.3800969

    PubMed  CAS  Google Scholar 

  • Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, Nobel A, Parker J, Ewend MG, Sawyer LR, Wu J, Liu Y, Nanda R, Tretiakova M, Ruiz Orrico A, Dreher D, Palazzo JP, Perreard L, Nelson E, Mone M, Hansen H, Mullins M, Quackenbush JF, Ellis MJ, Olopade OI, Bernard PS, Perou CM (2006) The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7:96. doi:10.1186/1471-2164-7-96

    PubMed  Google Scholar 

  • Hughes-Davies L, Huntsman D, Ruas M, Fuks F, Bye J, Chin SF, Milner J, Brown LA, Hsu F, Gilks B, Nielsen T, Schulzer M, Chia S, Ragaz J, Cahn A, Linger L, Ozdag H, Cattaneo E, Jordanova ES, Schuuring E, Yu DS, Venkitaraman A, Ponder B, Doherty A, Aparicio S, Bentley D, Theillet C, Ponting CP, Caldas C, Kouzarides T (2003) EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115(5):523–535

    PubMed  CAS  Google Scholar 

  • Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65(16):7065–7070. doi:10.1158/0008-5472.CAN-05-1783

    PubMed  CAS  Google Scholar 

  • Jonsson G, Naylor TL, Vallon-Christersson J, Staaf J, Huang J, Ward MR, Greshock JD, Luts L, Olsson H, Rahman N, Stratton M, Ringner M, Borg A, Weber BL (2005) Distinct genomic profiles in hereditary breast tumors identified by array-based comparative genomic hybridization. Cancer Res 65(17):7612–7621. doi:10.1158/0008-5472.CAN-05-0570

    PubMed  Google Scholar 

  • Jonsson G, Staaf J, Vallon-Christersson J, Ringner M, Holm K, Hegardt C, Gunnarsson H, Fagerholm R, Strand C, Agnarsson BA, Kilpivaara O, Luts L, Heikkila P, Aittomaki K, Blomqvist C, Loman N, Malmstrom P, Olsson H, Johannsson OT, Arason A, Nevanlinna H, Barkardottir RB, Borg A (2010) Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics. Breast Cancer Res 12(3):R42. doi:10.1186/bcr2596bcr2596

    PubMed  Google Scholar 

  • Jonsson G, Staaf J, Vallon-Christersson J, Ringner M, Gruvberger-Saal SK, Saal LH, Holm K, Hegardt C, Arason A, Fagerholm R, Persson C, Grabau D, Johnsson E, Lovgren K, Magnusson L, Heikkila P, Agnarsson BA, Johannsson OT, Malmstrom P, Ferno M, Olsson H, Loman N, Nevanlinna H, Barkardottir RB, Borg A (2012) The retinoblastoma gene undergoes rearrangements in BRCA1-deficient basal-like breast cancer. Cancer Res 72(16):4028–4036. doi:10.1158/0008-5472.CAN-12-0097

    PubMed  Google Scholar 

  • Joosse SA, van Beers EH, Tielen IH, Horlings H, Peterse JL, Hoogerbrugge N, Ligtenberg MJ, Wessels LF, Axwijk P, Verhoef S, Hogervorst FB, Nederlof PM (2009) Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH. Breast Cancer Res Treat 116(3):479–489. doi:10.1007/s10549-008-0117-z

    PubMed  CAS  Google Scholar 

  • Joosse SA, Brandwijk KI, Mulder L, Wesseling J, Hannemann J, Nederlof PM (2011) Genomic signature of BRCA1 deficiency in sporadic basal-like breast tumors. Genes Chromosomes Cancer 50(2):71–81. doi:10.1002/gcc.20833

    PubMed  CAS  Google Scholar 

  • Joosse SA, Brandwijk KI, Devilee P, Wesseling J, Hogervorst FB, Verhoef S, Nederlof PM (2012) Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH. Breast Cancer Res Treat 132(2):379–389. doi:10.1007/s10549-010-1016-7

    PubMed  CAS  Google Scholar 

  • Kainu T, Juo SH, Desper R, Schaffer AA, Gillanders E, Rozenblum E, Freas-Lutz D, Weaver D, Stephan D, Bailey-Wilson J, Kallioniemi OP, Tirkkonen M, Syrjakoski K, Kuukasjarvi T, Koivisto P, Karhu R, Holli K, Arason A, Johannesdottir G, Bergthorsson JT, Johannsdottir H, Egilsson V, Barkardottir RB, Johannsson O, Haraldsson K, Sandberg T, Holmberg E, Gronberg H, Olsson H, Borg A, Vehmanen P, Eerola H, Heikkila P, Pyrhonen S, Nevanlinna H (2000) Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus. Proc Natl Acad Sci USA 97(17):9603–9608

    PubMed  CAS  Google Scholar 

  • Kallioniemi A, Kallioniemi OP, Piper J, Tanner M, Stokke T, Chen L, Smith HS, Pinkel D, Gray JW, Waldman FM (1994) Detection and mapping of amplified DNA sequences in breast cancer by comparative genomic hybridization. Proc Natl Acad Sci USA 91(6):2156–2160

    PubMed  CAS  Google Scholar 

  • Lakhani SR, Gusterson BA, Jacquemier J, Sloane JP, Anderson TJ, van de Vijver MJ, Venter D, Freeman A, Antoniou A, McGuffog L, Smyth E, Steel CM, Haites N, Scott RJ, Goldgar D, Neuhausen S, Daly PA, Ormiston W, McManus R, Scherneck S, Ponder BA, Futreal PA, Peto J, Stoppa-Lyonnet D, Bignon YJ, Stratton MR (2000) The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2. Clin Cancer Res 6(3):782–789

    PubMed  CAS  Google Scholar 

  • Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, Easton DF (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318

    PubMed  CAS  Google Scholar 

  • Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, Bishop T, Benitez J, Rivas C, Bignon YJ, Chang-Claude J, Hamann U, Cornelisse CJ, Devilee P, Beckmann MW, Nestle-Kramling C, Daly PA, Haites N, Varley J, Lalloo F, Evans G, Maugard C, Meijers-Heijboer H, Klijn JG, Olah E, Gusterson BA, Pilotti S, Radice P, Scherneck S, Sobol H, Jacquemier J, Wagner T, Peto J, Stratton MR, McGuffog L, Easton DF (2005) Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11(14):5175–5180. doi:1078-0432.CCR-04-2424

    PubMed  CAS  Google Scholar 

  • Leggett BA, Young JP, Barker M (2003) Peutz-Jeghers syndrome: genetic screening. Expert Rev Anticancer Ther 3(4):518–524. doi:10.1586/14737140.3.4.518

    PubMed  CAS  Google Scholar 

  • Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, Asselin-Labat ML, Gyorki DE, Ward T, Partanen A, Feleppa F, Huschtscha LI, Thorne HJ, Fox SB, Yan M, French JD, Brown MA, Smyth GK, Visvader JE, Lindeman GJ (2009) Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med 15(8):907–913. doi:10.1038/nm.2000

    PubMed  CAS  Google Scholar 

  • Lips EH, Laddach N, Savola SP, Vollebergh MA, Oonk AM, Imholz AL, Wessels LF, Wesseling J, Nederlof PM, Rodenhuis S (2011) Quantitative copy number analysis by Multiplex Ligation-dependent Probe Amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness. Breast Cancer Res 13(5):R107. doi:10.1186/bcr3049bcr3049

    PubMed  CAS  Google Scholar 

  • Loo LW, Grove DI, Williams EM, Neal CL, Cousens LA, Schubert EL, Holcomb IN, Massa HF, Glogovac J, Li CI, Malone KE, Daling JR, Delrow JJ, Trask BJ, Hsu L, Porter PL (2004) Array comparative genomic hybridization analysis of genomic alterations in breast cancer subtypes. Cancer Res 64(23):8541–8549. doi:10.1158/0008-5472.CAN-04-1992

    PubMed  CAS  Google Scholar 

  • Loughrey M, Provan PJ, Byth K, Balleine RL (2008) Histopathological features of ‘BRCAX’ familial breast cancers in the kConFab resource. Pathology 40(4):352–358. doi:10.1080/00313020802035899

    PubMed  CAS  Google Scholar 

  • Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, Bowden G, Kalmyrzaev B, Warren-Perry M, Snape K, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, Rogers MT, Shanley S, Walker L, Eccles D, Evans DG, Renwick A, Seal S, Lord CJ, Ashworth A, Reis-Filho JS, Antoniou AC, Rahman N (2011) Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43(9):879–882. doi:10.1038/ng.893ng.893

    PubMed  CAS  Google Scholar 

  • Maguire P, Holmberg K, Kost-Alimova M, Imreh S, Skoog L, Lindblom A (2005) CGH analysis of familial non-BRCA1/BRCA2 breast tumors and mutation screening of a candidate locus on chromosome 17q11.2-12. Int J Mol Med 16(1):135–141

    PubMed  CAS  Google Scholar 

  • Manie E, Vincent-Salomon A, Lehmann-Che J, Pierron G, Turpin E, Warcoin M, Gruel N, Lebigot I, Sastre-Garau X, Lidereau R, Remenieras A, Feunteun J, Delattre O, de The H, Stoppa-Lyonnet D, Stern MH (2009) High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors. Cancer Res 69(2):663–671. doi:10.1158/0008-5472.CAN-08-1560

    PubMed  CAS  Google Scholar 

  • Martinez-Delgado B, Yanowsky K, Inglada-Perez L, Domingo S, Urioste M, Osorio A, Benitez J (2011) Genetic anticipation is associated with telomere shortening in hereditary breast cancer. PLoS Genet 7(7):e1002182. doi:10.1371/journal.pgen.1002182

    PubMed  CAS  Google Scholar 

  • Martinez-Delgado B, Yanowsky K, Inglada-Perez L, de la Hoya M, Caldes T, Vega A, Blanco A, Martin T, Gonzalez-Sarmiento R, Blasco M, Robledo M, Urioste M, Song H, Pharoah P, Benitez J (2012) Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporadic cases. J Med Genet 49(5):341–344. doi:10.1136/jmedgenet-2012-100807

    PubMed  Google Scholar 

  • Martins FC, De S, Almendro V, Gonen M, Park SY, Blum JL, Herlihy W, Ethington G, Schnitt SJ, Tung N, Garber JE, Fetten K, Michor F, Polyak K (2012) Evolutionary pathways in BRCA1-associated breast tumors. Cancer Discov 2(6):503–511. doi:10.1158/2159-8290.CD-11-0325

    PubMed  CAS  Google Scholar 

  • Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31(1):55–59. doi:10.1038/ng879ng879

    PubMed  CAS  Google Scholar 

  • Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Muller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42(5):410–414. doi:10.1038/ng.569ng.569

    PubMed  CAS  Google Scholar 

  • Melchor L, Benitez J (2008) An integrative hypothesis about the origin and development of sporadic and familial breast cancer subtypes. Carcinogenesis 29(8):1475–1482. doi:10.1093/carcin/bgn157

    PubMed  CAS  Google Scholar 

  • Melchor L, Honrado E, Huang J, Alvarez S, Naylor TL, Garcia MJ, Osorio A, Blesa D, Stratton MR, Weber BL, Cigudosa JC, Rahman N, Nathanson KL, Benitez J (2007) Estrogen receptor status could modulate the genomic pattern in familial and sporadic breast cancer. Clin Cancer Res 13(24):7305–7313. doi:10.1158/1078-0432.CCR-07-0711

    PubMed  CAS  Google Scholar 

  • Melchor L, Honrado E, Garcia MJ, Alvarez S, Palacios J, Osorio A, Nathanson KL, Benitez J (2008) Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes. Oncogene 27(22):3165–3175. doi:10.1038/sj.onc.1210975

    PubMed  CAS  Google Scholar 

  • Michailidou K, Hall P, Gonzalez-Neira A, Ghoussaini M, Dennis J, Milne RL, Schmidt MK, Chang-Claude J, Bojesen SE, Bolla MK, Wang Q, Dicks E, Lee A, Turnbull C, Rahman N, Fletcher O, Peto J, Gibson L, Dos Santos Silva I, Nevanlinna H, Muranen TA, Aittomaki K, Blomqvist C, Czene K, Irwanto A, Liu J, Waisfisz Q, Meijers-Heijboer H, Adank M, van der Luijt RB, Hein R, Dahmen N, Beckman L, Meindl A, Schmutzler RK, Muller-Myhsok B, Lichtner P, Hopper JL, Southey MC, Makalic E, Schmidt DF, Uitterlinden AG, Hofman A, Hunter DJ, Chanock SJ, Vincent D, Bacot F, Tessier DC, Canisius S, Wessels LF, Haiman CA, Shah M, Luben R, Brown J, Luccarini C, Schoof N, Humphreys K, Li J, Nordestgaard BG, Nielsen SF, Flyger H, Couch FJ, Wang X, Vachon C, Stevens KN, Lambrechts D, Moisse M, Paridaens R, Christiaens MR, Rudolph A, Nickels S, Flesch-Janys D, Johnson N, Aitken Z, Aaltonen K, Heikkinen T, Broeks A, Veer LJ, van der Schoot CE, Guenel P, Truong T, Laurent-Puig P, Menegaux F, Marme F, Schneeweiss A, Sohn C, Burwinkel B, Zamora MP, Perez JI, Pita G, Alonso MR, Cox A, Brock IW, Cross SS, Reed MW, Sawyer EJ, Tomlinson I, Kerin MJ, Miller N, Henderson BE, Schumacher F, Le Marchand L, Andrulis IL, Knight JA, Glendon G, Mulligan AM, Lindblom A, Margolin S, Hooning MJ, Hollestelle A, van den Ouweland AM, Jager A, Bui QM, Stone J, Dite GS, Apicella C, Tsimiklis H, Giles GG, Severi G, Baglietto L, Fasching PA, Haeberle L, Ekici AB, Beckmann MW, Brenner H, Muller H, Arndt V, Stegmaier C, Swerdlow A, Ashworth A, Orr N, Jones M, Figueroa J, Lissowska J, Brinton L, Goldberg MS, Labreche F, Dumont M, Winqvist R, Pylkas K, Jukkola-Vuorinen A, Grip M, Brauch H, Hamann U, Bruning T, Radice P, Peterlongo P, Manoukian S, Bonanni B, Devilee P, Tollenaar RA, Seynaeve C, van Asperen CJ, Jakubowska A, Lubinski J, Jaworska K, Durda K, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Bogdanova NV, Antonenkova NN, Dork T, Kristensen VN, Anton-Culver H, Slager S, Toland AE, Edge S, Fostira F, Kang D, Yoo KY, Noh DY, Matsuo K, Ito H, Iwata H, Sueta A, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Shu XO, Lu W, Gao YT, Cai H, Teo SH, Yip CH, Phuah SY, Cornes BK, Hartman M, Miao H, Lim WY, Sng JH, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Shen CY, Hsiung CN, Wu PE, Ding SL, Sangrajrang S, Gaborieau V, Brennan P, McKay J, Blot WJ, Signorello LB, Cai Q, Zheng W, Deming-Halverson S, Shrubsole M, Long J, Simard J, Garcia-Closas M, Pharoah PD, Chenevix-Trench G, Dunning AM, Benitez J, Easton DF (2013) Large-scale genotyping identifies 41 new loci associated with breast cancer risk. Nat Genet 45(4):353–361. doi:10.1038/ng.2563

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266(5182):66–71

    PubMed  CAS  Google Scholar 

  • Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, Mackay A, Grigoriadis A, Tutt A, Ashworth A, Reis-Filho JS, Smalley MJ (2010) BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7(3):403–417. doi:1016/j.stem.2010.07.010

    PubMed  CAS  Google Scholar 

  • Mulligan AM, Pinnaduwage D, Bane AL, Bull SB, O’Malley FP, Andrulis IL (2011) CK8/18 expression, the basal phenotype, and family history in identifying BRCA1-associated breast cancer in the Ontario site of the breast cancer family registry. Cancer 117(7):1350–1359. doi:10.1002/cncr.25642

    PubMed  CAS  Google Scholar 

  • Natrajan R, Mackay A, Lambros MB, Weigelt B, Wilkerson PM, Manie E, Grigoriadis A, A’Hern R, van der Groep P, Kozarewa I, Popova T, Mariani O, Turajlic S, Furney SJ, Marais R, Rodruigues DN, Flora AC, Wai P, Pawar V, McDade S, Carroll J, Stoppa-Lyonnet D, Green AR, Ellis IO, Swanton C, van Diest P, Delattre O, Lord CJ, Foulkes WD, Vincent-Salomon A, Ashworth A, Henri Stern M, Reis-Filho JS (2012) A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. J Pathol 227(1):29–41. doi:10.1002/path.4003

    PubMed  CAS  Google Scholar 

  • Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10(16):5367–5374. doi:10.1158/1078-0432.CCR-04-022010/16/5367

    PubMed  CAS  Google Scholar 

  • Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD, Raine K, Jones D, Hinton J, Marshall J, Stebbings LA, Menzies A, Martin S, Leung K, Chen L, Leroy C, Ramakrishna M, Rance R, Lau KW, Mudie LJ, Varela I, McBride DJ, Bignell GR, Cooke SL, Shlien A, Gamble J, Whitmore I, Maddison M, Tarpey PS, Davies HR, Papaemmanuil E, Stephens PJ, McLaren S, Butler AP, Teague JW, Jonsson G, Garber JE, Silver D, Miron P, Fatima A, Boyault S, Langerod A, Tutt A, Martens JW, Aparicio SA, Borg A, Salomon AV, Thomas G, Borresen-Dale AL, Richardson AL, Neuberger MS, Futreal PA, Campbell PJ, Stratton MR (2012a) Mutational processes molding the genomes of 21 breast cancers. Cell 149(5):979–993. doi:10.1016/j.cell.2012.04.024

    PubMed  CAS  Google Scholar 

  • Nik-Zainal S, Van Loo P, Wedge DC, Alexandrov LB, Greenman CD, Lau KW, Raine K, Jones D, Marshall J, Ramakrishna M, Shlien A, Cooke SL, Hinton J, Menzies A, Stebbings LA, Leroy C, Jia M, Rance R, Mudie LJ, Gamble SJ, Stephens PJ, McLaren S, Tarpey PS, Papaemmanuil E, Davies HR, Varela I, McBride DJ, Bignell GR, Leung K, Butler AP, Teague JW, Martin S, Jonsson G, Mariani O, Boyault S, Miron P, Fatima A, Langerod A, Aparicio SA, Tutt A, Sieuwerts AM, Borg A, Thomas G, Salomon AV, Richardson AL, Borresen-Dale AL, Futreal PA, Stratton MR, Campbell PJ (2012b) The life history of 21 breast cancers. Cell 149(5):994–1007. doi:10.1016/j.cell.2012.04.023

    PubMed  CAS  Google Scholar 

  • O’Donovan PJ, Livingston DM (2010) BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 31(6):961–967. doi:10.1093/carcin/bgq069

    PubMed  Google Scholar 

  • Oldenburg RA, Kroeze-Jansema K, Meijers-Heijboer H, van Asperen CJ, Hoogerbrugge N, van Leeuwen I, Vasen HF, Cleton-Jansen AM, Kraan J, Houwing-Duistermaat JJ, Morreau H, Cornelisse CJ, Devilee P (2006) Characterization of familial non-BRCA1/2 breast tumors by loss of heterozygosity and immunophenotyping. Clin Cancer Res 12(6):1693–1700. doi:10.1158/1078-0432.CCR-05-2230

    PubMed  CAS  Google Scholar 

  • Orr N, Lemnrau A, Cooke R, Fletcher O, Tomczyk K, Jones M, Johnson N, Lord CJ, Mitsopoulos C, Zvelebil M, McDade SS, Buck G, Blancher C, Trainer AH, James PA, Bojesen SE, Bokmand S, Nevanlinna H, Mattson J, Friedman E, Laitman Y, Palli D, Masala G, Zanna I, Ottini L, Giannini G, Hollestelle A, Ouweland AM, Novakovic S, Krajc M, Gago-Dominguez M, Castelao JE, Olsson H, Hedenfalk I, Easton DF, Pharoah PD, Dunning AM, Bishop DT, Neuhausen SL, Steele L, Houlston RS, Garcia-Closas M, Ashworth A, Swerdlow AJ (2012) Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk. Nat Genet 44(11):1182–1184. doi:10.1038/ng.2417ng.2417

    PubMed  CAS  Google Scholar 

  • Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A, Rodriguez S, Cigudosa JC, Diez O, Alonso C, Lerma E, Sanchez L, Rivas C, Benitez J (2003) Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin Cancer Res 9(10 Pt 1):3606–3614

    PubMed  CAS  Google Scholar 

  • Palacios J, Honrado E, Osorio A, Diez O, Rivas C, Benitez J (2004) Re: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 96 (9):712–714; author reply 714

    Google Scholar 

  • Palacios J, Honrado E, Osorio A, Cazorla A, Sarrio D, Barroso A, Rodriguez S, Cigudosa JC, Diez O, Alonso C, Lerma E, Dopazo J, Rivas C, Benitez J (2005) Phenotypic characterization of BRCA1 and BRCA2 tumors based in a tissue microarray study with 37 immunohistochemical markers. Breast Cancer Res Treat 90(1):5–14. doi:10.1007/s10549-004-1536-0

    PubMed  CAS  Google Scholar 

  • Palacios J, Robles-Frias MJ, Castilla MA, Lopez-Garcia MA, Benitez J (2008) The molecular pathology of hereditary breast cancer. Pathobiology 75(2):85–94. doi:10.1159/000123846

    PubMed  CAS  Google Scholar 

  • Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. doi:10.1038/35021093

    PubMed  CAS  Google Scholar 

  • Pharoah PD, Guilford P, Caldas C (2001) Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 121(6):1348–1353

    PubMed  CAS  Google Scholar 

  • Pinkel D, Albertson DG (2005) Array comparative genomic hybridization and its applications in cancer. Nat Genet 37(Suppl):S11–S17. doi:10.1038/ng1569

    PubMed  CAS  Google Scholar 

  • Popova T, Manie E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, Delattre O, Sigal-Zafrani B, Bollet M, Longy M, Houdayer C, Sastre-Garau X, Vincent-Salomon A, Stoppa-Lyonnet D, Stern MH (2012) Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72(21):5454–5462. doi:10.1158/0008-5472.CAN-12-14700008-5472.CAN-12-1470

    PubMed  CAS  Google Scholar 

  • Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Easton DF, Stratton MR (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39(2):165–167. doi:10.1038/ng1959

    PubMed  CAS  Google Scholar 

  • Rodriguez C, Hughes-Davies L, Valles H, Orsetti B, Cuny M, Ursule L, Kouzarides T, Theillet C (2004) Amplification of the BRCA2 pathway gene EMSY in sporadic breast cancer is related to negative outcome. Clin Cancer Res 10(17):5785–5791. doi:10.1158/1078-0432.CCR-03-041010/17/5785

    PubMed  CAS  Google Scholar 

  • Rosa-Rosa JM, Pita G, Urioste M, Llort G, Brunet J, Lazaro C, Blanco I, Ramon y Cajal T, Diez O, de la Hoya M, Caldes T, Tejada MI, Gonzalez-Neira A, Benitez J (2009) Genome-wide linkage scan reveals three putative breast-cancer-susceptibility loci. Am J Hum Genet 84 (2):115–122. doi:10.1016/j.ajhg.2008.12.013

    Google Scholar 

  • Roy R, Chun J, Powell SN (2012) BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 12(1):68–78. doi:10.1038/nrc3181nrc3181

    CAS  Google Scholar 

  • Ruark E, Snape K, Humburg P, Loveday C, Bajrami I, Brough R, Rodrigues DN, Renwick A, Seal S, Ramsay E, Duarte Sdel V, Rivas MA, Warren-Perry M, Zachariou A, Campion-Flora A, Hanks S, Murray A, Pour NA, Douglas J, Gregory L, Rimmer A, Walker NM, Yang TP, Adlard JW, Barwell J, Berg J, Brady AF, Brewer C, Brice G, Chapman C, Cook J, Davidson R, Donaldson A, Douglas F, Eccles D, Evans DG, Greenhalgh L, Henderson A, Izatt L, Kumar A, Lalloo F, Miedzybrodzka Z, Morrison PJ, Paterson J, Porteous M, Rogers MT, Shanley S, Walker L, Gore M, Houlston R, Brown MA, Caufield MJ, Deloukas P, McCarthy MI, Todd JA, Turnbull C, Reis-Filho JS, Ashworth A, Antoniou AC, Lord CJ, Donnelly P, Rahman N (2013) Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer. Nature 493(7432):406–410. doi:10.1038/nature11725

    PubMed  CAS  Google Scholar 

  • Saal LH, Gruvberger-Saal SK, Persson C, Lovgren K, Jumppanen M, Staaf J, Jonsson G, Pires MM, Maurer M, Holm K, Koujak S, Subramaniyam S, Vallon-Christersson J, Olsson H, Su T, Memeo L, Ludwig T, Ethier SP, Krogh M, Szabolcs M, Murty VV, Isola J, Hibshoosh H, Parsons R, Borg A (2008) Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet 40(1):102–107. doi:10.1038/ng.2007.39

    PubMed  CAS  Google Scholar 

  • Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, Chagtai T, Jayatilake H, Ahmed M, Spanova K, North B, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 38(11):1239–1241. doi:10.1038/ng1902

    PubMed  CAS  Google Scholar 

  • Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, Bashashati A, Prentice LM, Khattra J, Burleigh A, Yap D, Bernard V, McPherson A, Shumansky K, Crisan A, Giuliany R, Heravi-Moussavi A, Rosner J, Lai D, Birol I, Varhol R, Tam A, Dhalla N, Zeng T, Ma K, Chan SK, Griffith M, Moradian A, Cheng SW, Morin GB, Watson P, Gelmon K, Chia S, Chin SF, Curtis C, Rueda OM, Pharoah PD, Damaraju S, Mackey J, Hoon K, Harkins T, Tadigotla V, Sigaroudinia M, Gascard P, Tlsty T, Costello JF, Meyer IM, Eaves CJ, Wasserman WW, Jones S, Huntsman D, Hirst M, Caldas C, Marra MA, Aparicio S (2012) The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486(7403):395–399. doi:10.1038/nature10933

    PubMed  CAS  Google Scholar 

  • Shamseldin HE, Elfaki M, Alkuraya FS (2012) Exome sequencing reveals a novel Fanconi group defined by XRCC2 mutation. J Med Genet 49(3):184–186. doi:10.1136/jmedgenet-2011-100585

    PubMed  CAS  Google Scholar 

  • Shuen AY, Foulkes WD (2011) Inherited mutations in breast cancer genes–risk and response. J Mammary Gland Biol Neoplasia 16(1):3–15. doi:10.1007/s10911-011-9213-5

    PubMed  Google Scholar 

  • Smalley M, Ashworth A (2003) Stem cells and breast cancer: a field in transit. Nat Rev Cancer 3(11):832–844. doi:10.1038/nrc1212nrc1212

    PubMed  CAS  Google Scholar 

  • Smith HC, Bennett RP, Kizilyer A, McDougall WM, Prohaska KM (2012) Functions and regulation of the APOBEC family of proteins. Semin Cell Dev Biol 23(3):258–268. doi:10.1016/j.semcdb.2011.10.004

    PubMed  CAS  Google Scholar 

  • Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Lonning PE, Borresen-Dale AL (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98(19):10869–10874. doi:10.1073/pnas.19136709898/19/10869

    PubMed  CAS  Google Scholar 

  • Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, Demeter J, Perou CM, Lonning PE, Brown PO, Borresen-Dale AL, Botstein D (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 100(14):8418–8423. doi:10.1073/pnas.0932692100

    PubMed  CAS  Google Scholar 

  • Stacey SN, Manolescu A, Sulem P, Thorlacius S, Gudjonsson SA, Jonsson GF, Jakobsdottir M, Bergthorsson JT, Gudmundsson J, Aben KK, Strobbe LJ, Swinkels DW, van Engelenburg KC, Henderson BE, Kolonel LN, Le Marchand L, Millastre E, Andres R, Saez B, Lambea J, Godino J, Polo E, Tres A, Picelli S, Rantala J, Margolin S, Jonsson T, Sigurdsson H, Jonsdottir T, Hrafnkelsson J, Johannsson J, Sveinsson T, Myrdal G, Grimsson HN, Sveinsdottir SG, Alexiusdottir K, Saemundsdottir J, Sigurdsson A, Kostic J, Gudmundsson L, Kristjansson K, Masson G, Fackenthal JD, Adebamowo C, Ogundiran T, Olopade OI, Haiman CA, Lindblom A, Mayordomo JI, Kiemeney LA, Gulcher JR, Rafnar T, Thorsteinsdottir U, Johannsson OT, Kong A, Stefansson K (2008) Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 40(6):703–706. doi:10.1038/ng.131ng.131

    PubMed  CAS  Google Scholar 

  • Stefansson OA, Jonasson JG, Johannsson OT, Olafsdottir K, Steinarsdottir M, Valgeirsdottir S, Eyfjord JE (2009) Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes. Breast Cancer Res 11(4):R47. doi:10.1186/bcr2334

    PubMed  Google Scholar 

  • Stephens PJ, McBride DJ, Lin ML, Varela I, Pleasance ED, Simpson JT, Stebbings LA, Leroy C, Edkins S, Mudie LJ, Greenman CD, Jia M, Latimer C, Teague JW, Lau KW, Burton J, Quail MA, Swerdlow H, Churcher C, Natrajan R, Sieuwerts AM, Martens JW, Silver DP, Langerod A, Russnes HE, Foekens JA, Reis-Filho JS, van ‘t Veer L, Richardson AL, Borresen-Dale AL, Campbell PJ, Futreal PA, Stratton MR (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462 (7276):1005–1010. doi:10.1038/nature08645

    Google Scholar 

  • Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144(1):27–40. doi:10.1016/j.cell.2010.11.055

    PubMed  CAS  Google Scholar 

  • Tanic M, Yanowsky K, Rodriguez-Antona C, Andres R, Marquez-Rodas I, Osorio A, Benitez J, Martinez-Delgado B (2012a) Deregulated miRNAs in hereditary breast cancer revealed a role for miR-30c in regulating KRAS oncogene. PLoS ONE 7(6):e38847. doi:10.1371/journal.pone.0038847

    PubMed  CAS  Google Scholar 

  • Tanic M, Zajac M, Gomez-Lopez G, Benitez J, Martinez-Delgado B (2012b) Integration of BRCA1-mediated miRNA and mRNA profiles reveals microRNA regulation of TRAF2 and NFkappaB pathway. Breast Cancer Res Treat 134(1):41–51. doi:10.1007/s10549-011-1905-4

    PubMed  CAS  Google Scholar 

  • Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A, Byrd P, Taylor M, Easton DF (2005) Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst 97(11):813–822. doi:10.1093/jnci/dji141

    PubMed  CAS  Google Scholar 

  • Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H, Ingvarsson S, Karhu R, Tanner M, Isola J, Barkardottir RB, Borg A, Kallioniemi OP (1997) Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res 57(7):1222–1227

    PubMed  CAS  Google Scholar 

  • Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, Savage K, Gillett CE, Schmitt FC, Ashworth A, Tutt AN (2007) BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26(14):2126–2132. doi:10.1038/sj.onc.1210014

    PubMed  CAS  Google Scholar 

  • van Beers EH, van Welsem T, Wessels LF, Li Y, Oldenburg RA, Devilee P, Cornelisse CJ, Verhoef S, Hogervorst FB, van’t Veer LJ, Nederlof PM (2005) Comparative genomic hybridization profiles in human BRCA1 and BRCA2 breast tumors highlight differential sets of genomic aberrations. Cancer Res 65 (3):822–827

    Google Scholar 

  • van der Groep P, Bouter A, van der Zanden R, Siccama I, Menko FH, Gille JJ, van Kalken C, van der Wall E, Verheijen RH, van Diest PJ (2006) Distinction between hereditary and sporadic breast cancer on the basis of clinicopathological data. J Clin Pathol 59(6):611–617. doi:10.1136/jcp.2005.032151

    PubMed  Google Scholar 

  • van ‘t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415 (6871):530–536. doi:10.1038/415530a

  • Vargas AC, Reis-Filho JS, Lakhani SR (2011) Phenotype-genotype correlation in familial breast cancer. J Mammary Gland Biol Neoplasia 16(1):27–40. doi:10.1007/s10911-011-9204-6

    PubMed  Google Scholar 

  • Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM (2006) A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 103(7):2257–2261. doi:10.1073/pnas.0510565103

    PubMed  CAS  Google Scholar 

  • Waddell N, Arnold J, Cocciardi S, da Silva L, Marsh A, Riley J, Johnstone CN, Orloff M, Assie G, Eng C, Reid L, Keith P, Yan M, Fox S, Devilee P, Godwin AK, Hogervorst FB, Couch F, Grimmond S, Flanagan JM, Khanna K, Simpson PT, Lakhani SR, Chenevix-Trench G (2010a) Subtypes of familial breast tumours revealed by expression and copy number profiling. Breast Cancer Res Treat 123(3):661–677. doi:10.1007/s10549-009-0653-1

    PubMed  Google Scholar 

  • Waddell N, Cocciardi S, Johnson J, Healey S, Marsh A, Riley J, da Silva L, Vargas AC, Reid L, Simpson PT, Lakhani SR, Chenevix-Trench G (2010b) Gene expression profiling of formalin-fixed, paraffin-embedded familial breast tumours using the whole genome-DASL assay. J Pathol 221(4):452–461. doi:10.1002/path.2728

    PubMed  CAS  Google Scholar 

  • Wessels LF, van Welsem T, Hart AA, van’t Veer LJ, Reinders MJ, Nederlof PM (2002) Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res 62 (23):7110–7117

    Google Scholar 

  • Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D et al (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265(5181):2088–2090

    PubMed  CAS  Google Scholar 

  • Yanowsky K, Barroso A, Osorio A, Urioste M, Benitez J, Martinez-Delgado B (2012) Mutational analysis of telomere genes in BRCA1/2-negative breast cancer families with very short telomeres. Breast Cancer Res Treat 134(3):1337–1343. doi:10.1007/s10549-012-2141-2

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank all members of the Human Genetics Team for the last 10 years, who have been key in our advance in understanding familial breast cancer. We are grateful to the financial support from FIS PI12/0070 and INNPRONTA (MICIN) programmes.

Author information

Author notes

  1. Lorenzo Melchor

    Present address: Haemato-oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK

Authors and Affiliations

  1. Human Genetics Group, Programme of Human Cancer Genetics, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, Madrid, 28029, Spain

    Lorenzo Melchor & Javier Benítez

  2. Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain

    Javier Benítez

Authors
  1. Lorenzo Melchor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Javier Benítez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lorenzo Melchor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Melchor, L., Benítez, J. The complex genetic landscape of familial breast cancer. Hum Genet 132, 845–863 (2013). https://doi.org/10.1007/s00439-013-1299-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-013-1299-y

Keywords

Search

Navigation