Clinicopathological characterization and oncologic outcomes of metastatic small renal masses

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 of somatic mutations between matched primary and metastatic RCC tumors.

Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subject 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. Concordance score was calculated as (S-Pr)/(S+Pr). To calculate enrichment of private/shared mutations for a particular gene, we calculated a two-sided p-value from a binomial model for each gene with at least 10 somatic mutation events, and implemented a separate permutation test procedure. P-values were adjusted 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 (35%) pairs showed private mutations in both primary and metastasis. Of the remaining 39 (65%) pairs, 14 (23%) had private mutations specific to primary tumors, 12 (20%) had private mutations to metastases, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either primary or metastatic samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2. We observed that patients who received therapy prior to sampling of the primary or metastatic tissue had higher concordance of mutations between P-M pairs than patients who did not (Mann-Whitney p-value 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 primary or metastatic tumors, the prognostic and predictive value of mutations in primary vs. metastasis warrants further investigation.