Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations

David Brown, Dominiek Smeets, Borbála Székely, Denis Larsimont, A. Marcell Szász, Pierre-Yves Adnet, Françoise Rothé, Ghizlane Rouas, Zsófia I. Nagy, Zsófia Faragó, Anna-Mária Tőkés, Magdolna Dank, Gyöngyvér Szentmártoni, Nóra Udvarhelyi, Gabriele Zoppoli, Lajos Pusztai, Martine Piccart, Janina Kulka, Diether Lambrechts, Christos Sotiriou () and Christine Desmedt ()
Additional contact information
David Brown: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles
Dominiek Smeets: Laboratory of Translational Genetics, Vesalius Research Center, VIB
Borbála Székely: Semmelweis University
Denis Larsimont: Institut Jules Bordet
A. Marcell Szász: Semmelweis University
Pierre-Yves Adnet: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles
Françoise Rothé: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles
Ghizlane Rouas: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles
Zsófia I. Nagy: Semmelweis University
Zsófia Faragó: Semmelweis University
Anna-Mária Tőkés: Semmelweis University
Magdolna Dank: Semmelweis University Cancer Center, Semmelweis University
Gyöngyvér Szentmártoni: Semmelweis University Cancer Center, Semmelweis University
Nóra Udvarhelyi: Surgical and Molecular Tumor Pathology Centre, National Institute of Oncology
Gabriele Zoppoli: University of Genova and Istituto di Cura a Carattere Clinico e Scientifico Azienda Ospedaliera Universitaria San Martino—Instituto Nazionale Tumori
Lajos Pusztai: Yale University
Martine Piccart: Institut Jules Bordet, Université Libre de Bruxelles
Janina Kulka: Semmelweis University
Diether Lambrechts: Laboratory of Translational Genetics, Vesalius Research Center, VIB
Christos Sotiriou: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles
Christine Desmedt: Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common ‘metastatic precursor’. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination.

Date: 2017
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DOI: 10.1038/ncomms14944

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