Advertisement

Breast Cancer Research and Treatment

, Volume 102, Issue 2, pp 143–155 | Cite as

Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases

  • Lurdes Torres
  • Franclim R. Ribeiro
  • Nikos Pandis
  • Johan A. Andersen
  • Sverre Heim
  • Manuel R. Teixeira
Preclinical Study

Abstract

Conflicting theories of epithelial carcinogenesis disagree on the clonal composition of primary tumors and on the time at which metastases occur. In order to study the spatial distribution of disparate clonal populations within breast carcinomas and the extent of the genetic relationship between primary tumors and regional metastases, we have analyzed by comparative genomic hybridization 122 tissue samples from altogether 60 breast cancer patients, including 34 tumor samples obtained from different quadrants of 9 breast carcinomas, as well as paired primary-metastatic samples from 12 patients. The median intratumor genetic heterogeneity score (HS) was 17.4% and unsupervised hierarchical clustering analysis comparing the genetic features to those of an independent series of 41 breast carcinomas confirmed intratumor clonal divergence in a high proportion of cases. The median HS between paired primary breast tumors and lymph node metastases was 33.3%, but the number of genomic imbalances did not differ significantly. Clustering analysis confirmed extensive clonal divergence between primary carcinomas and lymph node metastases in several cases. In the independent series of 41 breast carcinomas, the number of genomic imbalances in primary tumors was significantly higher in patients presenting lymph node metastases (median = 15.5) than in the group with no evidence of disease spreading at diagnosis (median = 5.0). We conclude that primary breast carcinomas may be composed of several genetically heterogeneous and spatially separated cell populations and that paired primary breast tumors and lymph node metastases often present divergent clonal evolution, indicating that metastases may occur relatively early during breast carcinogenesis.

Keywords

Breast cancer Comparative genomic hybridization Intratumor genetic heterogeneity Primary tumor Lymph node metastasis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Notes

Acknowledgments

F.R.R. is a fellow of Fundação para a Ciência e a Tecnologia. L.T. is a fellow of Liga Portuguesa Contra o Cancro, Centro Regional do Norte. The financial support of Liga Portuguesa Contra o Cancro, Centro Regional do Norte, and the Norwegian Cancer Society is gratefully acknowledged.

References

  1. 1.
    Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28PubMedCrossRefGoogle Scholar
  2. 2.
    Heim S, Mandahl N, Mitelman F (1988) Genetic convergence and divergence in tumor progression. Cancer Res 48:5911–5916PubMedGoogle Scholar
  3. 3.
    Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602PubMedCrossRefGoogle Scholar
  4. 4.
    Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4:448–456PubMedCrossRefGoogle Scholar
  5. 5.
    Teixeira MR, Pandis N, Heim S (2002) Cytogenetic clues to breast carcinogenesis. Genes Chromosomes Cancer 33:1–16PubMedCrossRefGoogle Scholar
  6. 6.
    Teixeira MR, Pandis N, Bardi G et al (1995) Clonal heterogeneity in breast cancer: karyotypic comparisons of multiple intra- and extra-tumorous samples from 3 patients. Int J Cancer 63:63–68PubMedCrossRefGoogle Scholar
  7. 7.
    Teixeira MR, Pandis N, Bardi G et al (1996) Karyotypic comparisons of multiple tumorous and macroscopically normal surrounding tissue samples from patients with breast cancer. Cancer Res 56:855–859PubMedGoogle Scholar
  8. 8.
    Pandis N, Teixeira MR, Adeyinka A et al (1998) Cytogenetic comparison of primary tumors and lymph node metastases in breast cancer patients. Genes Chromosomes Cancer 22:122–129PubMedCrossRefGoogle Scholar
  9. 9.
    Nishizaki T, DeVries S, Chew K et al (1997) Genetic alterations in primary breast cancers and their metastases: direct comparison using modified comparative genomic hybridization. Genes Chromosomes Cancer 19:267–272PubMedCrossRefGoogle Scholar
  10. 10.
    Kuukasjarvi T, Karhu R, Tanner M et al (1997) Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Cancer Res 57:1597–1604PubMedGoogle Scholar
  11. 11.
    Sobin LH (1981) Histological typing of breast tumors, 2nd edn. World Health Organization, GenevaGoogle Scholar
  12. 12.
    Kallioniemi OP, Kallioniemi A, Piper J et al (1994) Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors. Genes Chromosomes Cancer 10:231–243PubMedCrossRefGoogle Scholar
  13. 13.
    Teixeira MR, Ribeiro FR, Torres L et al (2004) Assessment of clonal relationships in ipsilateral and bilateral multiple breast carcinomas by comparative genomic hybridisation and hierarchical clustering analysis. Br J Cancer 91:775–782PubMedGoogle Scholar
  14. 14.
    Kirchhoff M, Gerdes T, Rose H et al (1998) Detection of chromosomal gains and losses in comparative genomic hybridization analysis based on standard reference intervals. Cytometry 31:163–173PubMedCrossRefGoogle Scholar
  15. 15.
    ISCN (1995) An international system for human cytogenetic nomenclature. S. Karger, BaselGoogle Scholar
  16. 16.
    Waldman FM, DeVries S, Chew KL et al (2000) Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences. J Natl Cancer Inst 92:313–320PubMedCrossRefGoogle Scholar
  17. 17.
    Chen LC, Kurisu W, Ljung BM et al (1992) Heterogeneity for allelic loss in human breast cancer. J Natl Cancer Inst 84:506–510PubMedCrossRefGoogle Scholar
  18. 18.
    Aubele M, Mattis A, Zitzelsberger H et al (1999) Intratumoral heterogeneity in breast carcinoma revealed by laser-microdissection and comparative genomic hybridization. Cancer Genet Cytogenet 110:94–102PubMedCrossRefGoogle Scholar
  19. 19.
    Beerman H, Smit VT, Kluin PM et al (1991) Flow cytometric analysis of DNA stemline heterogeneity in primary and metastatic breast cancer. Cytometry 12:147–154PubMedCrossRefGoogle Scholar
  20. 20.
    Barranco SC, Perry RR, Durm ME et al (1994) Intratumor variability in prognostic indicators may be the cause of conflicting estimates of patient survival and response to therapy. Cancer Res 54:5351–5356PubMedGoogle Scholar
  21. 21.
    Arnerlov C, Emdin SO, Cajander S et al (2001) Intratumoral variations in DNA ploidy and s-phase fraction in human breast cancer. Anal Cell Pathol 23:21–28PubMedGoogle Scholar
  22. 22.
    Braakhuis BJ, Tabor MP, Kummer JA et al (2003) A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63:1727–1730PubMedGoogle Scholar
  23. 23.
    Tomlinson IP (2001) Mutations in normal breast tissue and breast tumours. Breast Cancer Res 3:299–303PubMedCrossRefGoogle Scholar
  24. 24.
    Steinarsdottir M, Jonasson JG, Vidarsson H et al (2004) Cytogenetic changes in nonmalignant breast tissue. Genes Chromosomes Cancer 41:47–55PubMedCrossRefGoogle Scholar
  25. 25.
    Deng G, Lu Y, Zlotnikov G, Thor AD et al (1996) Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 274:2057–2059PubMedCrossRefGoogle Scholar
  26. 26.
    Lakhani SR, Chaggar R, Davies S et al (1999) Genetic alterations in ‘normal’ luminal and myoepithelial cells of the breast. J Pathol 189:496–503PubMedCrossRefGoogle Scholar
  27. 27.
    Li Z, Moore DH, Meng ZH et al (2002) Increased risk of local recurrence is associated with allelic loss in normal lobules of breast cancer patients. Cancer Res 62:1000–1003PubMedGoogle Scholar
  28. 28.
    Braakhuis BJ, Leemans CR, Brakenhoff RH (2004) Using tissue adjacent to carcinoma as a normal control: an obvious but questionable practice. J Pathol 203:620–621PubMedCrossRefGoogle Scholar
  29. 29.
    Aubele M, Auer G, Braselmann H et al (2002) Chromosomal imbalances are associated with metastasis-free survival in breast cancer patients. Anal Cell Pathol 24:77–87PubMedGoogle Scholar
  30. 30.
    Hislop RG, Pratt N, Stocks SC et al (2002) Karyotypic aberrations of chromosomes 16 and 17 are related to survival in patients with breast cancer. Br J Surg 89:1581–1586PubMedCrossRefGoogle Scholar
  31. 31.
    Zudaire I, Odero MD, Caballero C et al (2002) Genomic imbalances detected by comparative genomic hybridization are prognostic markers in invasive ductal breast carcinomas. Histopathology 40:547–555PubMedCrossRefGoogle Scholar
  32. 32.
    Isola JJ, Kallioniemi OP, Chu LW et al (1995) Genetic aberrations detected by comparative genomic hybridization predict outcome in node-negative breast cancer. Am J Pathol 147:905–911PubMedGoogle Scholar
  33. 33.
    Hermsen MA, Baak JP, Meijer GA et al (1998) Genetic analysis of 53 lymph node-negative breast carcinomas by CGH and relation to clinical, pathological, morphometric, and DNA cytometric prognostic factors. J Pathol 186:356–362PubMedCrossRefGoogle Scholar
  34. 34.
    Dellas A, Torhorst J, Schultheiss E et al (2002) DNA sequence losses on chromosomes 11p and 18q are associated with clinical outcome in lymph node-negative ductal breast cancer. Clin Cancer Res 8:1210–1216PubMedGoogle Scholar
  35. 35.
    Teixeira MR, Tsarouha H, Kraggerud SM et al (2001) Evaluation of breast cancer polyclonality by combined chromosome banding and comparative genomic hybridization analysis. Neoplasia 3:204–214PubMedCrossRefGoogle Scholar
  36. 36.
    Kleivi K, Lothe RA, Heim S et al (2002) Genome profiling of breast cancer cells selected against in vitro shows copy number changes. Genes Chromosomes Cancer 33:304–309PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Lurdes Torres
    • 1
  • Franclim R. Ribeiro
    • 1
  • Nikos Pandis
    • 2
  • Johan A. Andersen
    • 3
  • Sverre Heim
    • 4
    • 5
  • Manuel R. Teixeira
    • 1
    • 6
  1. 1.Department of GeneticsPortuguese Oncology Institute PortoPortugal
  2. 2.Department of GeneticsSaint Savas HospitalAthensGreece
  3. 3.Department of PathologyOdense University HospitalOdenseDenmark
  4. 4.Department of Medical GeneticsRikshospitalet-Radiumhospitalet Medical CenterOsloNorway
  5. 5.Medical FacultyUniversity of OsloOsloNorway
  6. 6.Institute of Biomedical SciencesUniversity of PortoPortoPortugal

Personalised recommendations