Skip to main content

Genome-wide copy number alterations in subtypes of invasive breast cancers in young white and African American women

Breast Cancer Research and Treatment volume 127, pages 297–308 (2011)Cite this article

Abstract

Genomic copy number alterations (CNA) are common in breast cancer. Identifying characteristic CNAs associated with specific breast cancer subtypes is a critical step in defining potential mechanisms of disease initiation and progression. We used genome-wide array comparative genomic hybridization to identify distinctive CNAs in breast cancer subtypes from 259 young (diagnosed with breast cancer at <55 years) African American (AA) and Caucasian American (CA) women originally enrolled in a larger population-based study. We compared the average frequency of CNAs across the whole genome for each breast tumor subtype and found that estrogen receptor (ER)-negative tumors had a higher average frequency of genome-wide gain (P < 0.0001) and loss (P = 0.02) compared to ER-positive tumors. Triple-negative (TN) tumors had a higher average frequency of genome-wide gain (P < 0.0001) and loss (P = 0.003) than non-TN tumors. No significant difference in CNA frequency was observed between HER2-positive and -negative tumors. We also identified previously unreported recurrent CNAs (frequency >40%) for TN breast tumors at 10q, 11p, 11q, 16q, 20p, and 20q. In addition, we report CNAs that differ in frequency between TN breast tumors of AA and CA women. This is of particular relevance because TN breast cancer is associated with higher mortality and young AA women have higher rates of TN breast tumors compared to CA women. These data support the possibility that higher overall frequency of genomic alteration events as well as specific focal CNAs in TN breast tumors might contribute in part to the poor breast cancer prognosis for young AA women.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J, Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC (2006) Race, breast cancer subtypes, and survival in the Carolina breast cancer study. JAMA 295(21):2492–2502. doi:295/21/2492[pii]10.1001/jama.295.21.2492

    PubMed  Article  CAS  Google Scholar 

  2. 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, 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  CAS  Google Scholar 

  3. 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.09326921000932692100[pii]

    PubMed  Article  CAS  Google Scholar 

  4. Yu K, Lee CH, Tan PH, Tan P (2004) Conservation of breast cancer molecular subtypes and transcriptional patterns of tumor progression across distinct ethnic populations. Clin Cancer Res 10(16):5508–5517. doi:10.1158/1078-0432.CCR-04-008510/16/5508[pii]

    PubMed  Article  CAS  Google Scholar 

  5. Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, Perou CM, Nielsen TO (2008) Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14(5):1368–1376. doi:14/5/1368[pii]10.1158/1078-0432.CCR-07-1658

    PubMed  Article  CAS  Google Scholar 

  6. Abd El-Rehim DM, Ball G, Pinder SE, Rakha E, Paish C, Robertson JF, Macmillan D, Blamey RW, Ellis IO (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3):340–350. doi:10.1002/ijc.21004

    PubMed  Article  CAS  Google Scholar 

  7. Abd El-Rehim DM, Pinder SE, Paish CE, Bell J, Blamey RW, Robertson JF, Nicholson RI, Ellis IO (2004) Expression of luminal and basal cytokeratins in human breast carcinoma. J Pathol 203(2):661–671. doi:10.1002/path.1559

    PubMed  Article  Google Scholar 

  8. Diaz LK, Cryns VL, Symmans WF, Sneige N (2007) Triple negative breast carcinoma and the basal phenotype: from expression profiling to clinical practice. Adv Anat Pathol 14(6):419–430. doi:10.1097/PAP.0b013e318159473300125480-200711000-00004[pii]

    PubMed  Article  CAS  Google Scholar 

  9. Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V (2007) Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California cancer registry. Cancer 109(9):1721–1728. doi:10.1002/cncr.22618

    PubMed  Article  Google Scholar 

  10. Lund MJ, Trivers KF, Porter PL, Coates RJ, Leyland-Jones B, Brawley OW, Flagg EW, O’Regan RM, Gabram SG, Eley JW (2009) Race and triple negative threats to breast cancer survival: a population-based study in Atlanta, GA. Breast Cancer Res Treat 113(2):357–370. doi:10.1007/s10549-008-9926-3

    PubMed  Article  Google Scholar 

  11. Lund MJ, Butler EN, Bumpers HL, Okoli J, Rizzo M, Hatchett N, Green VL, Brawley OW, Oprea-Ilies GM, Gabram SG (2008) High prevalence of triple-negative tumors in an urban cancer center. Cancer 113(3):608–615. doi:10.1002/cncr.23569

    PubMed  Article  Google Scholar 

  12. Amend K, Hicks D, Ambrosone CB (2006) Breast cancer in African-American women: differences in tumor biology from European-American women. Cancer Res 66(17):8327–8330. doi:66/17/8327[pii]10.1158/0008-5472.CAN-06-1927

    PubMed  Article  CAS  Google Scholar 

  13. Chlebowski RT, Chen Z, Anderson GL, Rohan T, Aragaki A, Lane D, Dolan NC, Paskett ED, McTiernan A, Hubbell FA, Adams-Campbell LL, Prentice R (2005) Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J Natl Cancer Inst 97(6):439–448

    PubMed  Article  Google Scholar 

  14. Dayal HH, Power RN, Chiu C (1982) Race and socio-economic status in survival from breast cancer. J Chronic Dis 35(8):675–683

    PubMed  Article  CAS  Google Scholar 

  15. Eley JW, Hill HA, Chen VW, Austin DF, Wesley MN, Muss HB, Greenberg RS, Coates RJ, Correa P, Redmond CK et al (1994) Racial differences in survival from breast cancer. Results of the national cancer institute black/white cancer survival study. JAMA 272(12):947–954

    PubMed  Article  CAS  Google Scholar 

  16. Newman LA, Griffith KA, Jatoi I, Simon MS, Crowe JP, Colditz GA (2006) Meta-analysis of survival in African American and White American patients with breast cancer: ethnicity compared with socioeconomic status. J Clin Oncol 24(9):1342–1349. doi:24/9/1342[pii]10.1200/JCO.2005.03.3472

    PubMed  Article  Google Scholar 

  17. Shavers VL, Harlan LC, Stevens JL (2003) Racial/ethnic variation in clinical presentation, treatment, and survival among breast cancer patients under age 35. Cancer 97(1):134–147. doi:10.1002/cncr.11051

    PubMed  Article  Google Scholar 

  18. 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

    PubMed  Article  CAS  Google Scholar 

  19. 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

    PubMed  Article  CAS  Google Scholar 

  20. 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

    PubMed  Article  Google Scholar 

  21. 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

    PubMed  Article  CAS  Google Scholar 

  22. Brinton LA, Potischman NA, Swanson CA, Schoenberg JB, Coates RJ, Gammon MD, Malone KE, Stanford JL, Daling JR (1995) Breastfeeding and breast cancer risk. Cancer Causes Control 6(3):199–208

    PubMed  Article  CAS  Google Scholar 

  23. Porter PL, Lund MJ, Lin MG, Yuan X, Liff JM, Flagg EW, Coates RJ, Eley JW (2004) Racial differences in the expression of cell cycle-regulatory proteins in breast carcinoma. Cancer 100(12):2533–2542

    PubMed  Article  Google Scholar 

  24. Glogovac JK, Porter PL, Banker DE, Rabinovitch PS (1996) Cytokeratin labeling of breast cancer cells extracted from paraffin-embedded tissue for bivariate flow cytometric analysis. Cytometry 24(3):260–267. doi:10.1002/(SICI)1097-0320(19960701)24:3<260::AID-CYTO9>3.0.CO;2-L

    Google Scholar 

  25. Loo LW, Ton C, Wang YW, Grove DI, Bouzek H, Vartanian N, Lin MG, Yuan X, Lawton TL, Daling JR, Malone KE, Li CI, Hsu L, Porter PL (2008) Differential patterns of allelic loss in estrogen receptor-positive infiltrating lobular and ductal breast cancer. Genes Chromosomes Cancer 47(12):1049–1066. doi:10.1002/gcc.20610

    PubMed  Article  CAS  Google Scholar 

  26. Lieb JD, Liu X, Botstein D, Brown PO (2001) Promoter-specific binding of Rap1 revealed by genome-wide maps of protein–DNA association. Nat Genet 28(4):327–334. doi:10.1038/ng569ng569[pii]

    PubMed  Article  CAS  Google Scholar 

  27. Yang MC, Ruan QG, Yang JJ, Eckenrode S, Wu S, McIndoe RA, She JX (2001) A statistical method for flagging weak spots improves normalization and ratio estimates in microarrays. Physiol Genomics 7(1):45–53. doi:7/1/45[pii]

    PubMed  CAS  Google Scholar 

  28. Hsu L, Self SG, Grove D, Randolph T, Wang K, Delrow JJ, Loo L, Porter P (2005) Denoising array-based comparative genomic hybridization data using wavelets. Biostatistics 6(2):211–226. doi:6/2/211[pii]10.1093/biostatistics/kxi004

    PubMed  Article  Google Scholar 

  29. Trivers KF, Lund MJ, Porter PL, Liff JM, Flagg EW, Coates RJ, Eley JW (2009) The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control 20(7):1071–1082. doi:10.1007/s10552-009-9331-1

    PubMed  Article  Google Scholar 

  30. 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  Article  CAS  Google Scholar 

  31. 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

    PubMed  CAS  Google Scholar 

  32. Adelaide J, Finetti P, Bekhouche I, Repellini L, Geneix J, Sircoulomb F, Charafe-Jauffret E, Cervera N, Desplans J, Parzy D, Schoenmakers E, Viens P, Jacquemier J, Birnbaum D, Bertucci F, Chaffanet M (2007) Integrated profiling of basal and luminal breast cancers. Cancer Res 67(24):11565–11575. doi:67/24/11565[pii]10.1158/0008-5472.CAN-07-2536

    PubMed  Article  CAS  Google Scholar 

  33. Han W, Jung EM, Cho J, Lee JW, Hwang KT, Yang SJ, Kang JJ, Bae JY, Jeon YK, Park IA, Nicolau M, Jeffrey SS, Noh DY (2008) DNA copy number alterations and expression of relevant genes in triple-negative breast cancer. Genes Chromosomes Cancer 47(6):490–499. doi:10.1002/gcc.20550

    PubMed  Article  CAS  Google Scholar 

  34. Bergamaschi A, Kim YH, Kwei KA, La Choi Y, Bocanegra M, Langerod A, Han W, Noh DY, Huntsman DG, Jeffrey SS, Borresen-Dale AL, Pollack JR (2008) CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer. Mol Oncol 2(4):327–339. doi:S1574-7891(08)00124-5[pii]10.1016/j.molonc.2008.09.004

    PubMed  Article  Google Scholar 

  35. Thompson EW, Paik S, Brunner N, Sommers CL, Zugmaier G, Clarke R, Shima TB, Torri J, Donahue S, Lippman ME et al (1992) Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. J Cell Physiol 150(3):534–544. doi:10.1002/jcp.1041500314

    PubMed  Article  CAS  Google Scholar 

  36. Deming SL, Nass SJ, Dickson RB, Trock BJ (2000) C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance. Br J Cancer 83(12):1688–1695. doi:10.1054/bjoc.2000.1522S0007092000915222[pii]

    PubMed  Article  CAS  Google Scholar 

  37. Letessier A, Sircoulomb F, Ginestier C, Cervera N, Monville F, Gelsi-Boyer V, Esterni B, Geneix J, Finetti P, Zemmour C, Viens P, Charafe-Jauffret E, Jacquemier J, Birnbaum D, Chaffanet M (2006) Frequency, prognostic impact, and subtype association of 8p12, 8q24, 11q13, 12p13, 17q12, and 20q13 amplifications in breast cancers. BMC Cancer 6:245. doi:1471-2407-6-245[pii]10.1186/1471-2407-6-245

    PubMed  Article  Google Scholar 

  38. Melchor L, Saucedo-Cuevas LP, Munoz-Repeto I, Rodriguez-Pinilla SM, Honrado E, Campoverde A, Palacios J, Nathanson KL, Garcia MJ, Benitez J (2009) Comprehensive characterization of the DNA amplification at 13q34 in human breast cancer reveals TFDP1 and CUL4A as likely candidate target genes. Breast Cancer Res 11(6):R86. doi:bcr2456[pii]10.1186/bcr2456

    PubMed  Article  Google Scholar 

  39. Abba MC, Fabris VT, Hu Y, Kittrell FS, Cai WW, Donehower LA, Sahin A, Medina D, Aldaz CM (2007) Identification of novel amplification gene targets in mouse and human breast cancer at a syntenic cluster mapping to mouse ch8A1 and human ch13q34. Cancer Res 67(9):4104–4112. doi:67/9/4104[pii]10.1158/0008-5472.CAN-06-4672

    PubMed  Article  CAS  Google Scholar 

  40. Schindl M, Gnant M, Schoppmann SF, Horvat R, Birner P (2007) Overexpression of the human homologue for Caenorhabditis elegans cul-4 gene is associated with poor outcome in node-negative breast cancer. Anticancer Res 27(2):949–952

    PubMed  CAS  Google Scholar 

  41. Parise CA, Bauer KR, Brown MM, Caggiano V (2009) Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999–2004. Breast J 15(6):593–602. doi:TBJ822[pii]10.1111/j.1524-4741.2009.00822.x

    PubMed  Article  Google Scholar 

  42. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116(2):281–297. doi:S0092867404000455[pii]

    PubMed  Article  CAS  Google Scholar 

  43. Grady WM, Carethers JM (2008) Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135(4):1079–1099. doi:S0016-5085(08)01451-0[pii]10.1053/j.gastro.2008.07.076

    PubMed  Article  CAS  Google Scholar 

  44. Albain KS, Unger JM, Crowley JJ, Coltman CA Jr, Hershman DL (2009) Racial disparities in cancer survival among randomized clinical trials patients of the southwest oncology group. J Natl Cancer Inst 101(14):984–992. doi:djp175[pii]10.1093/jnci/djp175

    PubMed  Article  Google Scholar 

  45. Menashe I, Anderson WF, Jatoi I, Rosenberg PS (2009) Underlying causes of the black–white racial disparity in breast cancer mortality: a population-based analysis. J Natl Cancer Inst 101(14):993–1000. doi:djp176[pii]10.1093/jnci/djp176

    PubMed  Article  Google Scholar 

  46. Martin DN, Boersma BJ, Yi M, Reimers M, Howe TM, Yfantis HG, Tsai YC, Williams EH, Lee DH, Stephens RM, Weissman AM, Ambs S (2009) Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLoS One 4(2):e4531. doi:10.1371/journal.pone.0004531

    PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Stephanie Stafford for assistance with data management and analysis, the leadership and staff of the FHCRC DNA Array Facility and Jeri Glogovac for flow sorting of tumor samples. The study was supported by funding from NCI RO1 CA64292, P. I. William Eley; NCI R01 CA098415, P. I. Peggy Porter.

Conflict of interest

All authors report no conflict of interest associated with this study.

Author information

Author notes

  1. Lenora W. M. Loo

    Present address: Epidemiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI, USA

Affiliations

  1. Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N C1-015, Seattle, WA, 98109, USA

    Lenora W. M. Loo, Erin M. Flynn & Peggy L. Porter

  2. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Yinghui Wang, Li Hsu & Peggy L. Porter

  3. Department of Pathology, University of Washington, Seattle, WA, USA

    Peggy L. Porter

  4. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA

    Mary Jo Lund & Jonathan M. Liff

  5. Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA

    Erin J. Aiello Bowles & Diana S. M. Buist

  6. Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA

    Elaine W. Flagg

  7. National Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, GA, USA

    Ralph J. Coates

  8. Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA

    Mary Jo Lund & J. William Eley

Authors
  1. Lenora W. M. Loo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yinghui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erin M. Flynn
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary Jo Lund
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erin J. Aiello Bowles
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Diana S. M. Buist
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jonathan M. Liff
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elaine W. Flagg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ralph J. Coates
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. William Eley
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Li Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Peggy L. Porter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peggy L. Porter.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Loo, L.W.M., Wang, Y., Flynn, E.M. et al. Genome-wide copy number alterations in subtypes of invasive breast cancers in young white and African American women. Breast Cancer Res Treat 127, 297–308 (2011). https://doi.org/10.1007/s10549-010-1297-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-010-1297-x

Keywords

  • Breast cancer
  • Triple negative
  • Genomic alteration
  • Array comparative genomic hybridization
  • Young women