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.
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Authors | 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 |
Journal | European urology focus
(Eur Urol Focus)
Vol. 4
Issue 6
Pg. 986-994
(12 2018)
ISSN: 2405-4569 [Electronic] Netherlands |
PMID | 29066084
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Histone Demethylases
- KDM5C protein, human
- Histone-Lysine N-Methyltransferase
- SETD2 protein, human
- Von Hippel-Lindau Tumor Suppressor Protein
- PTEN Phosphohydrolase
- PTEN protein, human
- VHL protein, human
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Topics |
- Adrenal Gland Neoplasms
(genetics, secondary)
- Adult
- Aged
- Bone Neoplasms
(genetics, secondary)
- Carcinoma, Renal Cell
(genetics, secondary)
- Female
- Genomics
- High-Throughput Nucleotide Sequencing
- Histone Demethylases
(genetics)
- Histone-Lysine N-Methyltransferase
(genetics)
- Humans
- Kidney Neoplasms
(genetics, pathology)
- Lung Neoplasms
(genetics, secondary)
- Lymph Nodes
(pathology)
- Male
- Middle Aged
- PTEN Phosphohydrolase
(genetics)
- Precision Medicine
- Retroperitoneal Space
- Sequence Analysis, DNA
- Von Hippel-Lindau Tumor Suppressor Protein
(genetics)
- Young Adult
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