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.