Comparative genomic profiling of matched primary and metastatic tumors in renal cell carcinoma Journal Article


Authors: Becerra, M. F.; Reznik, E.; Redzematovic, A.; Tennenbaum, D. M.; Kashan, M.; Ghanaat, M.; Casuscelli, J.; Manley, B.; Jonsson, P.; DiNatale, R. G.; Blum, K. A.; Durack, J. C.; Solomon, S. B.; Arcila, M. E.; Bourque, C.; Socci, N.; Carlo, M. I.; Lee, C. H.; Voss, M. H.; Feldman, D. R.; Motzer, R. J.; Coleman, J. A.; Russo, P.; Cheng, E. H.; Hakimi, A. A.; Hsieh, J. J.
Article Title: Comparative genomic profiling of matched primary and metastatic tumors in renal cell carcinoma
Abstract: Using next-generation sequencing, we determined mutation discordance for cancer genes between matched primary and metastatic tumor samples from patients with renal cell carcinoma. As most precision cancer medicine administers targeted agents on the basis of mutations detected in primary tumors, further investigation into the genomic discordance between primary and metastatic tumor pairs is warranted. © 2017 European Association of Urology 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. © 2017 European Association of Urology
Keywords: adult; controlled study; aged; primary tumor; gene mutation; major clinical study; somatic mutation; exon; gene; metastasis; wild type; renal cell carcinoma; germ line; dna; genomics; discordance; next generation sequencing; next-generation sequencing; setd2 gene; human; male; female; article; convergent evolution; primary-metastasis tumor pairs; spatiotemporal divergence
Journal Title: European Urology Focus
Volume: 4
Issue: 6
ISSN: 2405-4569
Publisher: European Association of Urology  
Date Published: 2018-12-01
Start Page: 986
End Page: 994
Language: English
DOI: 10.1016/j.euf.2017.09.016
PUBMED: 29066084
PROVIDER: scopus
PMCID: PMC5910293
DOI/URL:
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Jonathan Coleman
    184 Coleman
  2. Paul Russo
    446 Russo
  3. Robert Motzer
    745 Motzer
  4. Darren Richard Feldman
    171 Feldman
  5. Martin Henner Voss
    126 Voss
  6. Stephen Solomon
    266 Solomon
  7. Nicholas D Socci
    182 Socci
  8. Emily H Cheng
    55 Cheng
  9. Maria Eugenia Arcila
    336 Arcila
  10. Jeremy Charles Durack
    84 Durack
  11. Abraham Ari Hakimi
    129 Hakimi
  12. Maria Isabel Carlo
    22 Carlo
  13. Eduard Reznik
    32 Reznik
  14. Chung-Han   Lee
    37 Lee
  15. Karl Philip Jonsson
    19 Jonsson
  16. Brandon John Manley
    21 Manley
  17. Maria Fernanda   Becerra
    15 Becerra
  18. Mahyar   Kashan
    7 Kashan
  19. Mazyar   Ghanaat
    10 Ghanaat
  20. Kyle Blum
    4 Blum