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Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma.

ABSTRACT: BACKGROUND:Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. OBJECTIVE:To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. DESIGN, SETTING, AND PARTICIPANTS: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. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: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. RESULTS AND LIMITATIONS: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). CONCLUSIONS: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. PATIENT SUMMARY: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.

SUBMITTER: Becerra MF

PROVIDER: S-EPMC5910293 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma.

Becerra Maria F MF Reznik Ed E Redzematovic Almedina A Tennenbaum Daniel M DM Kashan Mahyar M Ghanaat Mazyar M Casuscelli Jozefina J Manley Brandon B Jonsson Philip P DiNatale Renzo G RG Blum Kyle A KA Durack Jeremy C JC Solomon Stephen B SB Arcila Maria E ME Bourque Caitlin C Socci Nick N Carlo Maria I MI Lee Chung-Han CH Voss Martin H MH Feldman Darren R DR Motzer Robert J RJ Coleman Jonathan A JA Russo Paul P Cheng Emily H EH Hakimi A Ari AA Hsieh James J JJ

European urology focus 20171020 6

<h4>Background</h4>Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts.<h4>Objective</h4>To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors.<h4>Design, setting, and participants</h4>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 g ...[more]

PMID: 29066084

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Dataset Information

Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma.

Publications

Comparative Genomic Profiling of Matched Primary and Metastatic Tumors in Renal Cell Carcinoma.

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