Genetic heterogeneity in therapy-naïve synchronous primary breast cancers and their metastases Journal Article


Authors: Ng, C. K. Y.; Bidard, F. C.; Piscuoglio, S.; Geyer, F. C.; Lim, R. S.; de Bruijn, I.; Shen, R.; Pareja, F.; Berman, S. H.; Wang, L.; Pierga, J. Y.; Vincent-Salomon, A.; Viale, A.; Norton, L.; Sigal, B.; Weigelt, B.; Cottu, P.; Reis-Filho, J. S.
Article Title: Genetic heterogeneity in therapy-naïve synchronous primary breast cancers and their metastases
Abstract: Purpose: Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with de novo metastatic disease who had not received local or systemic therapy. Experimental Design: Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods. Results: Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%–95%) of shared somatic mutations. Although mutations in known driver genes including TP53, PIK3CA, and GATA3 were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition–related genes, including SMAD4, TCF7L2, and TCF4 (ITF2), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases. Conclusions: Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity. ©2017 AACR.
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 15
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-08-01
Start Page: 4402
End Page: 4415
Language: English
DOI: 10.1158/1078-0432.ccr-16-3115
PROVIDER: scopus
PUBMED: 28351929
PMCID: PMC5768571
DOI/URL:
Notes: Article -- Export Date: 5 September 2017 -- Source: Scopus
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MSK Authors
  1. Larry Norton
    563 Norton
  2. Ronglai Shen
    127 Shen
  3. Lu Wang
    139 Wang
  4. Agnes Viale
    205 Viale
  5. Samuel Hart Berman
    17 Berman
  6. Britta Weigelt
    260 Weigelt
  7. Jorge Sergio Reis
    283 Reis
  8. Francois-Clement Bidard
    17 Bidard
  9. Kiu Yan Charlotte Ng
    152 Ng
  10. Raymond Sear Lim
    54 Lim