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Multiple metastatic clones assessed by an integrative multiomics strategy in clear cell renal carcinoma: a case study
  1. Julien Dagher1,2,
  2. Angelique Brunot1,3,
  3. Bertrand Evrard1,
  4. Solene-Florence Kammerer-Jacquet2,
  5. Marion Beaumont4,
  6. Laurence Cornevin4,
  7. Fanny Derquin3,
  8. Gregory Verhoest5,
  9. Karim Bensalah5,
  10. Alexandra Lespagnol6,
  11. Frederic Dugay4,
  12. Marc-Antoine Belaud-Rotureau1,4,
  13. Frédéric Chalmel1,
  14. Nathalie Rioux-Leclercq1,2
  1. 1 Univ Rennes, Inserm, EHESP, Irset - UMR_S1085, F-35000, Rennes 1 University, Rennes, Bretagne, France
  2. 2 Department of Pathology, University Hospital, Rennes, Bretagne, France
  3. 3 Department of Oncology, University Hospital of Rennes, Rennes, France
  4. 4 Department of Cytogenetics and Cell Biology, CHU de Rennes, Rennes, France
  5. 5 Department of Urology, University Hospital of Rennes, Rennes, France
  6. 6 Department of Molecular Biology, CHU de Rennes, Rennes, France
  1. Correspondence to Dr Frédéric Chalmel, Univ Rennes, Inserm, EHESP, Irset - UMR_S1085, F-35000, Rennes 1 University, Rennes, Bretagne, France; frederic.chalmel{at}


The dynamics of metastatic evolution in clear cell renal cell carcinoma (ccRCC) are complex. We report a case study where tumour heterogeneity resulting from clonal evolution is a frequent feature and could play a role in metastatic dissemination.

We used an integrative multiomics strategy combining genomic and transcriptomic data to classify fourteen specimens from spatially different areas of a kidney tumour and three non-primary sites including a vein thrombus and two adrenal metastases.

All sites were heterogeneous and polyclonal, each tumour site containing two different aggressive subclonal populations, with differentially expressed genes implicated in distinct biological functions. These are rare primary metastatic samples prior to any medical treatment, where we showed a multiple metastatic seeding of two subclonal populations.

Multiple interdependent lineages could be the source of metastatic heterogeneity in ccRCC. By sampling metastases, patients with resistance to therapies could benefit a combination of targeted therapies based on more than one aggressive clone.

  • kidney neoplasms
  • neoplasm metastasis
  • neoplasms

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  • Handling editor Runjan Chetty.

  • FC and NR-L contributed equally.

  • Contributors JD, AB, NR-L and FC analysed and interpreted the patient data. JD, MB, LC, FDu and M-AB-R performed genomic analyses. JD and BE performed DNA and RNA extraction. AL and JD performed VHL gene analyses. FDe, GV and KB supplied clinical support. All authors read and approved the final manuscript.

  • Funding The authors would like to thank the Ligue Régionale Contre Le Cancer, Institut national du cancer (INCa). FC and BE were supported by the Institut National de la Santé Et de la Recherche Médicale (INSERM), the Université de Rennes one and the Ecole des Hautes Etudes en Santé Publique (EHESP - School of Public Health).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.