Patient-specific molecular alterations are associated with metastatic clear cell renal cell cancer progressing under tyrosine kinase inhibitor therapy
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Steffen Dietz1,*, Holger Sültmann1,*, YueJun Du2,3, Eva Reisinger4, Anja Lisa Riediger5, Anna-Lena Volckmar6, Albrecht Stenzinger6, Matthias Schlesner7, Dirk Jäger5, Markus Hohenfellner2, Stefan Duensing8, Carsten Grüllich5,* and Sascha Pahernik2,9,*
1Cancer Genome Research Group, German Cancer Consortium (DKTK), Heidelberg, Germany, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
2Department of Urology, Heidelberg University Hospital, Heidelberg, Germany
3Department of Urology, Nanfang Hospital of Southern Medical University, Guangzhou, China
4Data Management Group, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), and Heidelberg Center for Personalized Oncology (DKFZ-HIPO), Heidelberg, Germany
5Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany
6Institute of Pathology, University Hospital Heidelberg, and German Cancer Consortium (DKTK), Heidelberg, Germany
7Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany
8Section of Molecular Urooncology, Department of Urology, Heidelberg University Hospital, Heidelberg, Germany
9Department of Urology, Nuremberg General Hospital, Paracelsus Medical University, Nuremberg, Germany
*These authors contributed equally to this work
Holger Sültmann, email: [email protected]
Keywords: clonal evolution, metastatic clear cell renal cell carcinoma, next generation sequencing, therapy resistance, tyrosine kinase inhibitors
Received: March 16, 2017 Accepted: May 12, 2017 Published: May 23, 2017
The availability of tyrosine kinase inhibitors (TKI) during the past ten years has led to improved response and overall survival of patients suffering from metastatic clear cell renal cell carcinoma (ccRCC). However, most of these tumors will eventually progress due to resistance evolving under therapy. The objective of this pilot study was to determine whether molecular alterations in ccRCC tissues sampled over the course of the disease might be suggestive of potential therapies. We performed whole exome sequencing of nine samples from four patients in the MORE (Molecular Renal Cancer Evolution) trial. We analyzed the mutational patterns in the tissues at baseline and compared them to those detectable in biopsy samples after progression under TKI therapy. We found limited genetic concordance between primary and secondary tumor sites with private mutations in FLT4, MTOR, ITGA5, SETD2, PBRM1, and BRCA1 on progression. One patient who showed an increased mutational load in the metastasis responded to nivolumab treatment. Our data provide evidence for clonal evolution and diverse pathways leading to acquired TKI resistance of ccRCC. Acquired resistance to TKI in metastatic ccRCC is due to intra-tumor heterogeneity and clonal evolution of resistant subclones. Mutations occurring under progression might be informative for alternative targeted therapies.
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