Abstract
Background Differences in the clinical course and treatment responses in individual patients with advanced renal cell carcinoma (RCC) can largely be explained by the different genomics of this disease. To improve the personalized treatment strategy and survival outcomes for patients with advanced RCC, the genomic make-up in patients with advanced RCC was investigated to identify putative actionable mutations and signatures.
Methods In this prospective multicenter study (NCT01855477), whole-genome sequencing (WGS) data of locally advanced and metastatic tissue biopsies and matched whole-blood samples were collected from 91 patients with histopathologically confirmed RCC. WGS data were analyzed for small somatic variants, copy-number alterations and structural variants. For a subgroup of patients, RNA sequencing (RNA-Seq) data could be analyzed. RNA-Seq data were clustered on immunogenic and angiogenic gene expression patterns according to a previously developed angio-immunogenic gene signature.
Results For papillary and clear cell RCC, putative actionable drug targets were detected by WGS in 100% of the patients. RNA-Seq data of clear cell and papillary RCC were clustered using a previously developed angio-immunogenic gene signature. Analyses of driver mutations and RNA-Seq data revealed clear differences among different RCC subtypes, showing the added value of WGS and RNA-Seq over clinicopathological data.
Conclusions By improving both histological subtyping and the selection of treatment according to actionable targets and immune signatures, WGS and RNA-Seq may improve therapeutic decision making for most patients with advanced RCC, including patients with non-clear cell RCC for whom no standard treatment is available to data. Prospective clinical trials are needed to evaluate the impact of genomic and transcriptomic diagnostics on survival outcome for advanced RCC patients.
Competing Interest Statement
P.H. declares consultancy roles for Astellas, MSD, Ipsen, Pfizer, AstraZeneca, and Bristol-Myers Squibb, all outside the submitted work; H.M.W. declares honoraria from Roche and Astellas and travel expenses from Ipsen and Astellas, all outside the submitted work; S.F.O declares research grants from Novartis, Pfizer and Celldex Therapeutics and advisory board for Bristol Myers Squibb (all paid to the institution); M.L. declares speakers fee of BMS and advisory board of MSD, both paid to institution; R.H.J.M. declares speakers fee from Novartis and advisory role for Servier, patency from Pamgene, and investigator-initiated research (paid to institution) from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Pamgene, Pfizer, Novartis, Roche, Sanofi, Servier, all outside the submitted work; M.P.L. declares advisory board for Amgen, Astellas, Astra Zeneca, Bayer, INCa, Janssen Cilag BV, MSD, Novartis, Pfizer, Roche, Sanofi, Servier, consulting role for Julius Clinical and Research Grants (paid to institution) from Astellas, Janssen, MSD, Sanofi, all outside the submitted work; H.J.G.W. declares speakers honoraria from Bayer, Depositary receipts for shares from Cergentis B.V. all outside the submitted work; A.A.M.V. reports advisory board (all paid to institution) of BMS, MSD, Merck, Pfizer, Ipsen, Eisai, Pierre Fabre, Roche, Novartis, Sanofi, all outside the submitted work. All other authors declare no competing interests.
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