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Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes

Breast Cancer Research and Treatment volume 132, pages 439–448 (2012)Cite this article

Abstract

CHEK2 1100delC is a moderate-risk cancer susceptibility allele that confers a high breast cancer risk in a polygenic setting. Gene expression profiling of CHEK2 1100delC breast cancers may reveal clues to the nature of the polygenic CHEK2 model and its genes involved. Here, we report global gene expression profiles of a cohort of 155 familial breast cancers, including 26 CHEK2 1100delC mutant tumors. In line with previous work, all CHEK2 1100delC mutant tumors clustered among the hormone receptor-positive breast cancers. In the hormone receptor-positive subset, a 40-gene CHEK2 signature was subsequently defined that significantly associated with CHEK2 1100delC breast cancers. The identification of a CHEK2 gene signature implies an unexpected biological homogeneity among the CHEK2 1100delC breast cancers. In addition, all 26 CHEK2 1100delC tumors classified as luminal intrinsic subtype breast cancers, with 8 luminal A and 18 luminal B tumors. This biological make-up of CHEK2 1100delC breast cancers suggests that a relatively limited number of additional susceptibility alleles are involved in the polygenic CHEK2 model. Identification of these as-yet-unknown susceptibility alleles should be aided by clues from the 40-gene CHEK2 signature.

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References

  1. 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  Article  CAS  Google Scholar 

  2. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J, Collins N, Gregory S, Gumbs C, Micklem G (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378(6559):789–792

    PubMed  Article  CAS  Google Scholar 

  3. Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S, Merajver S, Thorlacius S, Offit K, Stoppa-Lyonnet D, Belanger C, Bell R, Berry S, Bogden R, Chen Q, Davis T, Dumont M, Frye C, Hattier T, Jammulapati S, Janecki T, Jiang P, Kehrer R, Leblanc JF, Goldgar DE et al (1996) The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet 12(3):333–337

    PubMed  Article  CAS  Google Scholar 

  4. Thompson D, Easton D (2004) The genetic epidemiology of breast cancer genes. J Mammary Gland Biol Neoplasia 9(3):221–236

    PubMed  Article  Google Scholar 

  5. Walsh T, King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11(2):103–105

    PubMed  Article  CAS  Google Scholar 

  6. 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 et al (2002) Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31(1):55–59

    PubMed  Article  CAS  Google Scholar 

  7. Vahteristo P, Bartkova J, Eerola H, Syrjakoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomaki K, Heikkila P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71(2):432–438

    PubMed  Article  CAS  Google Scholar 

  8. CBCC-C Consortium (2004) 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 74(6):1175–1182

    Article  Google Scholar 

  9. Nevanlinna H, Bartek J (2006) The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 25(43):5912–5919

    PubMed  Article  CAS  Google Scholar 

  10. Oldenburg RA, Kroeze-Jansema K, Kraan J, Morreau H, Klijn JG, Hoogerbrugge N, Ligtenberg MJ, van Asperen CJ, Vasen HF, Meijers C, Meijers-Heijboer H, de Bock TH, Cornelisse CJ, Devilee P (2003) The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 63(23):8153–8157

    PubMed  CAS  Google Scholar 

  11. Peto J (2002) Breast cancer susceptibility: a new look at an old model. Cancer Cell 1(5):411–412

    PubMed  Article  CAS  Google Scholar 

  12. Smith P, McGuffog L, Easton DF, Mann GJ, Pupo GM, Newman B, Chenevix-Trench G, Szabo C, Southey M, Renard H, Odefrey F, Lynch H, Stoppa-Lyonnet D, Couch F, Hopper JL, Giles GG, McCredie MR, Buys S, Andrulis I, Senie R, Goldgar DE, Oldenburg R, Kroeze-Jansema K, Kraan J, Meijers-Heijboer H et al (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45(7):646–655

    PubMed  Article  CAS  Google Scholar 

  13. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D, Breast Cancer Susceptibility C, Easton DF, Stratton MR, Rahman N (2006) ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet 38(8):873–875

    PubMed  Article  CAS  Google Scholar 

  14. 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, Breast Cancer Susceptibility C, 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

    PubMed  Article  CAS  Google Scholar 

  15. 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, Breast Cancer Susceptibility C, Easton DF, Stratton MR (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39(2):165–167

    PubMed  Article  CAS  Google Scholar 

  16. 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, Collaborators S, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le Marchand L, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY et al (2007) Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447(7148):1087–1093

    PubMed  Article  CAS  Google Scholar 

  17. Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, Wacholder S, Wang Z, Welch R, Hutchinson A, Wang J, Yu K, Chatterjee N, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Hayes RB, Tucker M et al (2007) A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet 39(7):870–874

    PubMed  Article  CAS  Google Scholar 

  18. Stacey SN, Manolescu A, Sulem P, Rafnar T, Gudmundsson J, Gudjonsson SA, Masson G, Jakobsdottir M, Thorlacius S, Helgason A, Aben KK, Strobbe LJ, Albers-Akkers MT, Swinkels DW, Henderson BE, Kolonel LN, Le Marchand L, Millastre E, Andres R, Godino J, Garcia-Prats MD, Polo E, Tres A, Mouy M, Saemundsdottir J et al (2007) Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet 39(7):865–869

    PubMed  Article  CAS  Google Scholar 

  19. Stacey SN, Gudbjartsson DF, Sulem P, Bergthorsson JT, Kumar R, Thorleifsson G, Sigurdsson A, Jakobsdottir M, Sigurgeirsson B, Benediktsdottir KR, Thorisdottir K, Ragnarsson R, Scherer D, Rudnai P, Gurzau E, Koppova K, Hoiom V, Botella-Estrada R, Soriano V, Juberias P, Grasa M, Carapeto FJ, Tabuenca P, Gilaberte Y, Gudmundsson J et al (2008) Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits. Nat Genet 40(11):1313–1318

    PubMed  Article  CAS  Google Scholar 

  20. Zheng W, Long J, Gao YT, Li C, Zheng Y, Xiang YB, Wen W, Levy S, Deming SL, Haines JL, Gu K, Fair AM, Cai Q, Lu W, Shu XO (2009) Genome-wide association study identifies a new breast cancer susceptibility locus at 6q25.1. Nat Genet 41(3):324–328

    PubMed  Article  CAS  Google Scholar 

  21. Thomas G, Jacobs KB, Kraft P, Yeager M, Wacholder S, Cox DG, Hankinson SE, Hutchinson A, Wang Z, Yu K, Chatterjee N, Garcia-Closas M, Gonzalez-Bosquet J, Prokunina-Olsson L, Orr N, Willett WC, Colditz GA, Ziegler RG, Berg CD, Buys SS, McCarty CA, Feigelson HS, Calle EE, Thun MJ, Diver R et al (2009) A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nat Genet 41(5):579–584

    PubMed  Article  CAS  Google Scholar 

  22. Ahmed S, Thomas G, Ghoussaini M, Healey CS, Humphreys MK, Platte R, Morrison J, Maranian M, Pooley KA, Luben R, Eccles D, Evans DG, Fletcher O, Johnson N, dos Santos Silva I, Peto J, Stratton MR, Rahman N, Jacobs K, Prentice R, Anderson GL, Rajkovic A, Curb JD, Ziegler RG, Berg CD et al (2009) Newly discovered breast cancer susceptibility loci on. 3p24 and 17q23.2. Nat Genet 41(5):585–590

    PubMed  Article  CAS  Google Scholar 

  23. Perou CM, Sørlie 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

    PubMed  Article  CAS  Google Scholar 

  24. Sørlie 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, Eystein Lonning P, 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

    PubMed  Article  Google Scholar 

  25. Sørlie 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

    PubMed  Article  Google Scholar 

  26. Hanash S (2004) Integrated global profiling of cancer. Nat Rev Cancer 4(8):638–644

    PubMed  Article  CAS  Google Scholar 

  27. Fan C, Oh DS, Wessels L, Weigelt B, Nuyten DS, Nobel AB, Van’t Veer LJ, Perou CM (2006) Concordance among gene-expression-based predictors for breast cancer. N Engl J Med 355(6):560–569

    PubMed  Article  CAS  Google Scholar 

  28. Sotiriou C, Pusztai L (2009) Gene-expression signatures in breast cancer. N Engl J Med 360(8):790–800

    PubMed  Article  CAS  Google Scholar 

  29. Oakman C, Bessi S, Zafarana E, Galardi F, Biganzoli L, Di Leo A (2009) Recent advances in systemic therapy: new diagnostics and biological predictors of outcome in early breast cancer. Breast Cancer Res 11(2):205

    PubMed  Article  Google Scholar 

  30. 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

    Article  Google Scholar 

  31. van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, Schreiber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteveen A, Glas A, Delahaye L, van der Velde T, Bartelink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R (2002) A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347(25):1999–2009

    PubMed  Article  Google Scholar 

  32. Ahr A, Karn T, Solbach C, Seiter T, Strebhardt K, Holtrich U, Kaufmann M (2002) Identification of high risk breast-cancer patients by gene expression profiling. Lancet 359(9301):131–132

    PubMed  Article  Google Scholar 

  33. Huang E, Cheng SH, Dressman H, Pittman J, Tsou MH, Horng CF, Bild A, Iversen ES, Liao M, Chen CM, West M, Nevins JR, Huang AT (2003) Gene expression predictors of breast cancer outcomes. Lancet 361(9369):1590–1596

    PubMed  Article  CAS  Google Scholar 

  34. Sotiriou C, Neo SY, McShane LM, Korn EL, Long PM, Jazaeri A, Martiat P, Fox SB, Harris AL, Liu ET (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA 100(18):10393–10398

    PubMed  Article  CAS  Google Scholar 

  35. Ma XJ, Wang Z, Ryan PD, Isakoff SJ, Barmettler A, Fuller A, Muir B, Mohapatra G, Salunga R, Tuggle JT, Tran Y, Tran D, Tassin A, Amon P, Wang W, Wang W, Enright E, Stecker K, Estepa-Sabal E, Smith B, Younger J, Balis U, Michaelson J, Bhan A, Habin K et al (2004) A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 5(6):607–616

    PubMed  Article  CAS  Google Scholar 

  36. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351(27):2817–2826

    PubMed  Article  CAS  Google Scholar 

  37. Ramaswamy S, Ross KN, Lander ES, Golub TR (2003) A molecular signature of metastasis in primary solid tumors. Nat Genet 33(1):49–54

    PubMed  Article  CAS  Google Scholar 

  38. Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Elledge R, Mohsin S, Osborne CK, Chamness GC, Allred DC, O’Connell P (2003) Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 362(9381):362–369

    PubMed  Article  CAS  Google Scholar 

  39. Wang Y, Klijn JG, Zhang Y, Sieuwerts AM, Look MP, Yang F, Talantov D, Timmermans M, Meijer-van Gelder ME, Yu J, Jatkoe T, Berns EM, Atkins D, Foekens JA (2005) Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365(9460):671–679

    PubMed  CAS  Google Scholar 

  40. Jansen MP, Foekens JA, van Staveren IL, Dirkzwager-Kiel MM, Ritstier K, Look MP, Meijer-van Gelder ME, Sieuwerts AM, Portengen H, Dorssers LC, Klijn JG, Berns EM (2005) Molecular classification of tamoxifen-resistant breast carcinomas by gene expression profiling. J Clin Oncol 23(4):732–740

    PubMed  Article  CAS  Google Scholar 

  41. Foekens JA, Atkins D, Zhang Y, Sweep FC, Harbeck N, Paradiso A, Cufer T, Sieuwerts AM, Talantov D, Span PN, Tjan-Heijnen VC, Zito AF, Specht K, Hoefler H, Golouh R, Schittulli F, Schmitt M, Beex LV, Klijn JG, Wang Y (2006) Multicenter validation of a gene expression-based prognostic signature in lymph node-negative primary breast cancer. J Clin Oncol 24(11):1665–1671

    PubMed  Article  CAS  Google Scholar 

  42. Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA, Booser D, Theriault RL, Buzdar AU, Dempsey PJ, Rouzier R, Sneige N, Ross JS, Vidaurre T, Gomez HL, Hortobagyi GN, Pusztai L (2006) Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol 24(26):4236–4244

    PubMed  Article  CAS  Google Scholar 

  43. 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 (2001) Gene-expression profiles in hereditary breast cancer. N Engl J Med 344(8):539–548

    PubMed  Article  CAS  Google Scholar 

  44. Dressman MA, Baras A, Malinowski R, Alvis LB, Kwon I, Walz TM, Polymeropoulos MH (2003) Gene expression profiling detects gene amplification and differentiates tumor types in breast cancer. Cancer Res 63(9):2194–2199

    PubMed  CAS  Google Scholar 

  45. Miller LD, Smeds J, George J, Vega VB, Vergara L, Ploner A, Pawitan Y, Hall P, Klaar S, Liu ET, Bergh J (2005) An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc Natl Acad Sci USA 102(38):13550–13555

    PubMed  Article  CAS  Google Scholar 

  46. Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, Joshi MB, Harpole D, Lancaster JM, Berchuck A, Olson JA Jr, Marks JR, Dressman HK, West M, Nevins JR (2006) Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439(7074):353–357

    PubMed  Article  CAS  Google Scholar 

  47. Adler AS, Lin M, Horlings H, Nuyten DS, van de Vijver MJ, Chang HY (2006) Genetic regulators of large-scale transcriptional signatures in cancer. Nat Genet 38(4):421–430

    PubMed  Article  CAS  Google Scholar 

  48. Verhoog LC, Brekelmans CT, Seynaeve C, van den Bosch LM, Dahmen G, van Geel AN, Tilanus-Linthorst MM, Bartels CC, Wagner A, van den Ouweland A, Devilee P, Meijers-Heijboer EJ, Klijn JG (1998) Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351(9099):316–321

    PubMed  Article  CAS  Google Scholar 

  49. 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  Article  CAS  Google Scholar 

  50. de Bock GH, Schutte M, Krol-Warmerdam EM, Seynaeve C, Blom J, Brekelmans CT, Meijers-Heijboer H, van Asperen CJ, Cornelisse CJ, Devilee P, Tollenaar RA, Klijn JG (2004) Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J Med Genet 41(10):731–735

    PubMed  Article  Google Scholar 

  51. Schmidt MK, Tollenaar RA, de Kemp SR, Broeks A, Cornelisse CJ, Smit VT, Peterse JL, van Leeuwen FE, Van’t Veer LJ (2007) Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol 25(1):64–69

    PubMed  Article  CAS  Google Scholar 

  52. Hickson ID (2003) RecQ helicases: caretakers of the genome. Nat Rev Cancer 3(3):169–178

    PubMed  Article  CAS  Google Scholar 

  53. Kitao S, Shimamoto A, Goto M, Miller RW, Smithson WA, Lindor NM, Furuichi Y (1999) Mutations in RECQL4 cause a subset of cases of Rothmund–Thomson syndrome. Nat Genet 22(1):82–84

    PubMed  Article  CAS  Google Scholar 

  54. Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, Ciocci S, Proytcheva M, German J (1995) The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 83(4):655–666

    PubMed  Article  CAS  Google Scholar 

  55. Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S, Martin GM, Mulligan J, Schellenberg GD (1996) Positional cloning of the Werner’s syndrome gene. Science 272(5259):258–262

    PubMed  Article  CAS  Google Scholar 

  56. Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, Mok SC, Randrianarison V, Brodie S, Salstrom J, Rasmussen TP, Klimke A, Marrese C, Marahrens Y, Deng CX, Feunteun J, Livingston DM (2002) BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell 111(3):393–405

    PubMed  Article  CAS  Google Scholar 

  57. Richardson AL, Wang ZC, De Nicolo A, Lu X, Brown M, Miron A, Liao X, Iglehart JD, Livingston DM, Ganesan S (2006) X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell 9(2):121–132

    PubMed  Article  CAS  Google Scholar 

  58. Wang J, Mager J, Chen Y, Schneider E, Cross JC, Nagy A, Magnuson T (2001) Imprinted X inactivation maintained by a mouse Polycomb group gene. Nat Genet 28(4):371–375

    PubMed  Article  CAS  Google Scholar 

  59. Silva J, Mak W, Zvetkova I, Appanah R, Nesterova TB, Webster Z, Peters AH, Jenuwein T, Otte AP, Brockdorff N (2003) Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. Dev Cell 4(4):481–495

    PubMed  Article  CAS  Google Scholar 

  60. Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408(6811):433–439

    PubMed  Article  CAS  Google Scholar 

  61. Bartek J, Falck J, Lukas J (2001) CHK2 kinase: a busy messenger. Nat Rev Mol Cell Biol 2(12):877–886

    PubMed  Article  CAS  Google Scholar 

  62. Moffa AB, Tannheimer SL, Ethier SP (2004) Transforming potential of alternatively spliced variants of fibroblast growth factor receptor 2 in human mammary epithelial cells. Mol Cancer Res 2(11):643–652

    PubMed  CAS  Google Scholar 

  63. Adnane J, Gaudray P, Dionne CA, Crumley G, Jaye M, Schlessinger J, Jeanteur P, Birnbaum D, Theillet C (1991) BEK and FLG, two receptors to members of the FGF family, are amplified in subsets of human breast cancers. Oncogene 6(4):659–663

    PubMed  CAS  Google Scholar 

  64. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O’Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K et al (2007) Patterns of somatic mutation in human cancer genomes. Nature 446(7132):153–158

    PubMed  Article  CAS  Google Scholar 

  65. Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW (2000) DNA damage-induced activation of p53 by the checkpoint kinase chk2. Science 287(5459):1824–1827

    PubMed  Article  CAS  Google Scholar 

  66. Chehab NH, Malikzay A, Appel M, Halazonetis TD (2000) Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Genes Dev 14(3):278–288

    PubMed  CAS  Google Scholar 

  67. Shieh SY, Ahn J, Tamai K, Taya Y, Prives C (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14(3):289–300

    PubMed  CAS  Google Scholar 

  68. Crook T, Crossland S, Crompton MR, Osin P, Gusterson BA (1997) p53 mutations in BRCA1-associated familial breast cancer. Lancet 350(9078):638–639

    PubMed  Article  CAS  Google Scholar 

  69. Crook T, Brooks LA, Crossland S, Osin P, Barker KT, Waller J, Philp E, Smith PD, Yulug I, Peto J, Parker G, Allday MJ, Crompton MR, Gusterson BA (1998) p53 mutation with frequent novel condons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours. Oncogene 17(13):1681–1689

    PubMed  Article  CAS  Google Scholar 

  70. Phillips KA, Nichol K, Ozcelik H, Knight J, Done SJ, Goodwin PJ, Andrulis IL (1999) Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations. J Natl Cancer Inst 91(5):469–473

    PubMed  Article  CAS  Google Scholar 

  71. Schuyer M, Berns EM (1999) Is TP53 dysfunction required for BRCA1-associated carcinogenesis? Mol Cell Endocrinol 155(1–2):143–152

    PubMed  Article  CAS  Google Scholar 

  72. Wasielewski M, Elstrodt F, Klijn JG, Berns EM, Schutte M (2006) Thirteen new p53 gene mutants identified among 41 human breast cancer cell lines. Breast Cancer Res Treat 99:97–101

    PubMed  Article  CAS  Google Scholar 

  73. Cortez D, Wang Y, Qin J, Elledge SJ (1999) Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286(5442):1162–1166

    PubMed  Article  CAS  Google Scholar 

  74. Lee JS, Collins KM, Brown AL, Lee CH, Chung JH (2000) hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404(6774):201–204

    PubMed  Article  CAS  Google Scholar 

  75. Meijers-Heijboer H, Wijnen J, Vasen H, Wasielewski M, Wagner A, Hollestelle A, Elstrodt F, van den Bos R, de Snoo A, Fat GT, Brekelmans C, Jagmohan S, Franken P, Verkuijlen P, van den Ouweland A, Chapman P, Tops C, Moslein G, Burn J, Lynch H, Klijn J, Fodde R, Schutte M (2003) The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72(5):1308–1314

    PubMed  Article  CAS  Google Scholar 

  76. McShane LM, Radmacher MD, Freidlin B, Yu R, Li MC, Simon R (2002) Methods for assessing reproducibility of clustering patterns observed in analyses of microarray data. Bioinformatics 18(11):1462–1469

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

We are grateful to the breast cancer patients and their clinicians for participation in this research. We thank Marion Meier-van Gelder, Mieke Timmermans, Miranda Arnold, Anneke Goedheer, Roberto Rodriguez-Garcia, Wendy van der Smissen, and Anja de Snoo for their technical assistance. We also thank Wim van Putten and Antoinette Hollestelle for insightful discussions. Funding : Dutch Cancer Society grants DDHK 2002-2687 and DDHK 2003-2862, and partly by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research NWO. Hanne Meijers-Heijboer is a fellow from the NWO Vidi Research Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Affiliations

  1. Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Center, PO Box 1738, 3000 DR, Rotterdam, The Netherlands

    Jord H. A. Nagel, Marcel Smid, Anieta M. Sieuwerts, Marijke Wasielewski, Vanja de Weerd, Anita M. A. C. Trapman-Jansen, Jan G. M. Klijn, John A. Foekens, John W. M. Martens, Mieke Schutte & Hanne Meijers-Heijboer

  2. Department of Bioinformatics, Erasmus University Medical Center, Rotterdam, The Netherlands

    Justine K. Peeters & Peter J. van der Spek

  3. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

    Ans van den Ouweland, Hennie Brüggenwirth & Hanne Meijers-Heijboer

  4. Erasmus Center for Biomics, Erasmus University Medical Center, Rotterdam, The Netherlands

    Wilfred F. J. van IJcken

  5. Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands

    Hanne Meijers-Heijboer

Authors
  1. Jord H. A. Nagel
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  2. Justine K. Peeters
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  3. Marcel Smid
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  4. Anieta M. Sieuwerts
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  7. Anita M. A. C. Trapman-Jansen
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  8. Ans van den Ouweland
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  9. Hennie Brüggenwirth
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  10. Wilfred F. J. van IJcken
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  11. Jan G. M. Klijn
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  12. Peter J. van der Spek
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  13. John A. Foekens
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  14. John W. M. Martens
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  15. Mieke Schutte
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  16. Hanne Meijers-Heijboer
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Corresponding author

Correspondence to John W. M. Martens.

Additional information

Jord H. A. Nagel, Justine K. Peeters, and Marcel Smid contributed equally to this work.

John W. M. Martens, Mieke Schutte, and Hanne Meijers-Heijboer contributed equally to this work.

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Nagel, J.H.A., Peeters, J.K., Smid, M. et al. Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes. Breast Cancer Res Treat 132, 439–448 (2012). https://doi.org/10.1007/s10549-011-1588-x

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  • DOI: https://doi.org/10.1007/s10549-011-1588-x

Keywords

  • Breast cancer
  • CHEK2 1100delC
  • Intrinsic subtypes