Germ cell tumor molecular heterogeneity revealed through analysis of primary and metastasis pairs

Michael L. Cheng, Mark T.A. Donoghue, François Audenet, Nathan C. Wong, Eugene J. Pietzak, Craig M. Bielski, Sumit Isharwal, Gopa Iyer, Samuel Funt, Aditya Bagrodia, Dean F. Bajorin, Victor E. Reuter, Jana Eng, Gabriella Joseph, Caitlin Bourque, Maria Bromberg, Lilan Ling, S. Duygu Selcuklu, Maria E. Arcila, Dana W.Y. TsuiAhmet Zehir, Agnes Viale, Michael F. Berger, George J. Bosl, Joel Sheinfeld, Eliezer van Allen, Barry S. Taylor, Hikmat Al-Ahmadie, David B. Solit, Darren R. Feldman

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

PURPOSE Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease. PATIENTS AND METHODS Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients. RESULTS The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). TP53 pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype. CONCLUSION Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in TP53 were clonal when present and shared among primary-metastasis pairs.

Original languageEnglish (US)
Pages (from-to)1307-1320
Number of pages14
JournalJCO Precision Oncology
Volume4
DOIs
StatePublished - 2020
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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