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

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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.

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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.

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Authors and Affiliations

  1. Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Lurdes Torres, Franclim R. Ribeiro & Manuel R. Teixeira

  2. Department of Genetics, Saint Savas Hospital, Athens, Greece

    Nikos Pandis

  3. Department of Pathology, Odense University Hospital, Odense, Denmark

    Johan A. Andersen

  4. Department of Medical Genetics, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway

    Sverre Heim

  5. Medical Faculty, University of Oslo, Oslo, Norway

    Sverre Heim

  6. Institute of Biomedical Sciences, University of Porto, Porto, Portugal

    Manuel R. Teixeira

Authors
  1. Lurdes Torres
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  2. Franclim R. Ribeiro
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  3. Nikos Pandis
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  4. Johan A. Andersen
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  5. Sverre Heim
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  6. Manuel R. Teixeira
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Correspondence to Manuel R. Teixeira.

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Torres, L., Ribeiro, F.R., Pandis, N. et al. Intratumor genomic heterogeneity in breast cancer with clonal divergence between primary carcinomas and lymph node metastases. Breast Cancer Res Treat 102, 143–155 (2007). https://doi.org/10.1007/s10549-006-9317-6

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  • DOI: https://doi.org/10.1007/s10549-006-9317-6

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