Breast Cancer Research and Treatment

, Volume 128, Issue 1, pp 23–30 | Cite as

Patterns and incidence of chromosomal instability and their prognostic relevance in breast cancer subtypes

  • Marcel Smid
  • Marlous Hoes
  • Anieta M. Sieuwerts
  • Stefan Sleijfer
  • Yi Zhang
  • Yixin Wang
  • John A. Foekens
  • John W. M. MartensEmail author
Preclinical study


One of the hallmarks of human solid tumors is chromosomal instability (CIN). We studied global patterns as well as individual levels of CIN and determined the prognostic relevance among breast cancer subtypes. For this, we used single nucleotide polymorphism copy number data of 313 primary lymph-node negative breast cancers. The level of CIN for individual samples was determined by counting the total number of chromosomal segments showing a gain or loss per specimen. Hierarchical clustering resulted in four groups showing distinct patterns of abnormalities, predominantly characterized by 1q gain, 8q gain, 1q&8q gain, or no gain of these loci. Estrogen receptor (ER)-positive and ER-negative samples showed an uneven distribution (statistically significant) across the cluster-groups, as did the molecular subtypes and triple-negative tumors (negative for estrogen-, progesterone-, and her2/neu-receptor). The CIN-score was significantly higher in ER-negative and triple-negative samples. Among luminal cancers, luminal B had a higher CIN-score than luminal A. The CIN-score was significantly associated with prognosis, measured by the time to distant metastasis, in ER-positive, luminal B, and her2/neu subtypes, but not in ER-negative patients. Our study points to a multifaceted role for CIN in breast cancer. Within ER-negative samples, CIN is likely related to the onset but other factors govern the progression of the disease. In contrast, CIN is clearly associated with progression in ER-positive, luminal B, and her2/neu subtypes; thus, assessing CIN in these subtypes may contribute to personalized patient management.


Chromosomal instability Subtypes Prognosis SNP copy number 



The study was supported by Veridex LLC for tissue processing and isolating RNA and DNA for microarray analysis as well as by a research grant from the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO). This organization had no role in study design, analysis of data or preparation of the manuscript.

Conflict of interest statement

Y. Zhang and Y. Wang are employees of, and hold stock in Veridex LLC, which financially supported this study for tissue processing and microarray analysis. The other authors declare no conflict of interest.

Supplementary material

10549_2010_1026_MOESM1_ESM.ppt (879 kb)
(PPT 877 kb)


  1. 1.
    Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396(6712):643–649PubMedCrossRefGoogle Scholar
  2. 2.
    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 Chromosom Cancer 45(11):1033–1040PubMedCrossRefGoogle Scholar
  3. 3.
    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):529–541PubMedCrossRefGoogle Scholar
  4. 4.
    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):2156–2160PubMedCrossRefGoogle Scholar
  5. 5.
    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):8541–8549PubMedCrossRefGoogle Scholar
  6. 6.
    Naylor TL, Greshock J, Wang Y, Colligon T, Yu QC, Clemmer V, Zaks TZ, Weber BL (2005) High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization. Breast Cancer Res 7(6):R1186–R1198PubMedCrossRefGoogle Scholar
  7. 7.
    Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO (1999) Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nat Genet 23(1):41–46PubMedCrossRefGoogle Scholar
  8. 8.
    Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, Richon C, Yan K, Wang B, Vassal G, Delaloge S, Hortobagyi GN, Symmans WF, Lazar V, Pusztai L (2009) Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res 15(2):441–451PubMedCrossRefGoogle Scholar
  9. 9.
    Carter SL, Eklund AC, Kohane IS, Harris LN, Szallasi Z (2006) A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers. Nat Genet 38(9):1043–1048PubMedCrossRefGoogle Scholar
  10. 10.
    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):1005–1010PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang Y, Martens JW, Yu JX, Jiang J, Sieuwerts AM, Smid M, Klijn JG, Wang Y, Foekens JA (2009) Copy number alterations that predict metastatic capability of human breast cancer. Cancer Res 69(9):3795–3801PubMedCrossRefGoogle Scholar
  12. 12.
    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):747–752PubMedCrossRefGoogle Scholar
  13. 13.
    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):5979–5984PubMedGoogle Scholar
  14. 14.
    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):530–536CrossRefGoogle Scholar
  15. 15.
    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):671–679PubMedGoogle Scholar
  16. 16.
    Yu JX, Sieuwerts AM, Zhang Y, Martens JW, Smid M, Klijn JG, Wang Y, Foekens JA (2007) Pathway analysis of gene signatures predicting metastasis of node-negative primary breast cancer. BMC Cancer 7:182PubMedCrossRefGoogle Scholar
  17. 17.
    McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCIEWGoCD (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst 97(16):1180–1184PubMedCrossRefGoogle Scholar
  18. 18.
    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):1665–1671PubMedCrossRefGoogle Scholar
  19. 19.
    Smid M, Wang Y, Zhang Y, Sieuwerts AM, Yu J, Klijn JG, Foekens JA, Martens JW (2008) Subtypes of breast cancer show preferential site of relapse. Cancer Res 68(9):3108–3114PubMedCrossRefGoogle Scholar
  20. 20.
    Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550PubMedCrossRefGoogle Scholar
  21. 21.
    Chang HY, Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, van de Rijn M, Botstein D, Brown PO (2004) Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. PLoS Biol 2(2):E7PubMedCrossRefGoogle Scholar
  22. 22.
    Chi JT, Wang Z, Nuyten DS, Rodriguez EH, Schaner ME, Salim A, Wang Y, Kristensen GB, Helland A, Borresen-Dale AL, Giaccia A, Longaker MT, Hastie T, Yang GP, van de Vijver MJ, Brown PO (2006) Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med 3(3):e47PubMedCrossRefGoogle Scholar
  23. 23.
    Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K, Clarke MF (2007) The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Engl J Med 356(3):217–226PubMedCrossRefGoogle Scholar
  24. 24.
    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):2817–2826PubMedCrossRefGoogle Scholar
  25. 25.
    Sotiriou C, Wirapati P, Loi S, Harris A, Fox S, Smeds J, Nordgren H, Farmer P, Praz V, Haibe-Kains B, Desmedt C, Larsimont D, Cardoso F, Peterse H, Nuyten D, Buyse M, Van de Vijver MJ, Bergh J, Piccart M, Delorenzi M (2006) Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst 98(4):262–272PubMedCrossRefGoogle Scholar
  26. 26.
    Winter SC, Buffa FM, Silva P, Miller C, Valentine HR, Turley H, Shah KA, Cox GJ, Corbridge RJ, Homer JJ, Musgrove B, Slevin N, Sloan P, Price P, West CM, Harris AL (2007) Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers. Cancer Res 67(7):3441–3449PubMedCrossRefGoogle Scholar
  27. 27.
    Goeman JJ, van de Geer SA, de Kort F, van Houwelingen HC (2004) A global test for groups of genes: testing association with a clinical outcome. Bioinformatics 20(1):93–99PubMedCrossRefGoogle Scholar
  28. 28.
    Tusher VG, Tibshirani R, Chu G (2001) Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98(9):5116–5121PubMedCrossRefGoogle Scholar
  29. 29.
    Schmidt M, Bohm D, von Torne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kolbl H, Gehrmann M (2008) The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 68(13):5405–5413PubMedCrossRefGoogle Scholar
  30. 30.
    Radmacher MD, McShane LM, Simon R (2002) A paradigm for class prediction using gene expression profiles. J Comput Biol 9(3):505–511PubMedCrossRefGoogle Scholar
  31. 31.
    Chin SF, Teschendorff AE, Marioni JC, Wang Y, Barbosa-Morais NL, Thorne NP, Costa JL, Pinder SE, van de Wiel MA, Green AR, Ellis IO, Porter PL, Tavare S, Brenton JD, Ylstra B, Caldas C (2007) High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer. Genome Biol 8(10):R215PubMedCrossRefGoogle Scholar
  32. 32.
    Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H, Spichtin H, Maurer R, Mirlacher M, Kochli O, Zuber M, Dieterich H, Mross F, Wilber K, Simon R, Sauter G (2004) Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res 64(23):8534–8540PubMedCrossRefGoogle Scholar
  33. 33.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedCrossRefGoogle Scholar
  34. 34.
    Ellsworth RE, Hooke JA, Love B, Kane JL, Patney HL, Ellsworth DL, Shriver CD (2008) Correlation of levels and patterns of genomic instability with histological grading of invasive breast tumors. Breast Cancer Res Treat 107(2):259–265PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Marcel Smid
    • 1
    • 2
  • Marlous Hoes
    • 1
  • Anieta M. Sieuwerts
    • 1
    • 2
  • Stefan Sleijfer
    • 1
  • Yi Zhang
    • 3
  • Yixin Wang
    • 3
  • John A. Foekens
    • 1
    • 2
  • John W. M. Martens
    • 1
    • 2
    Email author
  1. 1.Department of Medical Oncology, Josephine Nefkens InstituteErasmus MCRotterdamThe Netherlands
  2. 2.Cancer Genomics CentreErasmus MCRotterdamThe Netherlands
  3. 3.Veridex LLC, a Johnson & Johnson CompanyNorth RaritanUSA

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