Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts.
To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors.
Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture-based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline.
Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S-Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites.
Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2. We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p=0.088).
Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation.
In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.
European urology focus. 2017 Oct 20 [Epub ahead of print]
Maria F Becerra, Ed Reznik, Almedina Redzematovic, Daniel M Tennenbaum, Mahyar Kashan, Mazyar Ghanaat, Jozefina Casuscelli, Brandon Manley, Philip Jonsson, Renzo G DiNatale, Kyle A Blum, Jeremy C Durack, Stephen B Solomon, Maria E Arcila, Caitlin Bourque, Nick Socci, Maria I Carlo, Chung-Han Lee, Martin H Voss, Darren R Feldman, Robert J Motzer, Jonathan A Coleman, Paul Russo, Emily H Cheng, A Ari Hakimi, James J Hsieh
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Urology, Miller School of Medicine University of Miami, Miami, FL, USA., Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Urology, Ludwig-Maximilians University, Munich, Germany., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St. Louis, MO, USA. Electronic address: .