Germ Cell Tumors (MSK, J Clin Oncol 2016)

Overview

Bagrodia et al. performed whole-exome sequencing on a discovery cohort of 19 advanced germ cell tumors (GCTs) and validated findings with MSK-IMPACT targeted sequencing on 161 additional prospective patients at Memorial Sloan Kettering Cancer Center (combined N=180). The cohort was heavily enriched for the cisplatin-resistant phenotype to identify genomic determinants of resistance. All mutational and clinical data are publicly available on cBioPortal.

Composition

  • N = 180 men with advanced germ cell tumor receiving first-line cisplatin-based chemotherapy at MSK.
  • Discovery cohort: 19 tumors profiled by whole-exome sequencing (10 cisplatin-resistant, 9 cisplatin-sensitive); mean coverage 116× (range 93–134×).
  • Validation cohort: 161 prospective patients profiled by MSK-IMPACT (IMPACT410) targeted exon-capture (>300 cancer-related genes; 500–1,000× depth).
  • Histology: 70% NSGCT (n=126), 30% SEM (n=54).
  • Primary site: 87.2% testis (TT), 12.2% mediastinum, 0.6% retroperitoneum.
  • Cisplatin sensitivity: 76 sensitive vs 104 resistant.
  • IGCCCG risk: good 51.1%, intermediate 15.6%, poor 32.8%.
  • Reference genome: hg19.

Assays / panels (linked)

  • whole-exome-seq — discovery cohort (19 tumors); mean coverage 116×.
  • IMPACT410 — MSK-IMPACT targeted NGS of >300 cancer-related genes; 500–1,000× depth; validation cohort (161 patients).

Papers using this cohort

  • PMID:27646943 — Bagrodia et al., “Genetic Determinants of Cisplatin Resistance in Patients With Advanced Germ Cell Tumors,” Journal of Clinical Oncology 2016. (Defining study for this cohort.)

Notable findings derived from this cohort

  • TP53 alterations found exclusively in cisplatin-resistant tumors (17/104 [16.3%] vs 0/76 sensitive; P<.001); combined TP53/MDM2 pathway alterations present in 24.0% vs 2.6% (P<.001) of resistant vs sensitive tumors. PMID:27646943
  • TP53/MDM2 alteration independently predicted shorter progression-free survival (HR 1.83; 95% CI 1.12–2.98; P=.016) after adjusting for IGCCCG risk model. PMID:27646943
  • 72% of primary mediastinal nonseminomas harbored TP53 alterations (13/18), providing the first genetic basis for the dismal prognosis of this subgroup. PMID:27646943
  • Novel RAC1 hotspot mutations (G12V, G12R, P34R, Q61R, Q61K) identified in 9 patients (5% incidence — highest reported across cancer types in TCGA at publication); functionally validated to activate PAK1 and MEK1/2 phosphorylation. PMID:27646943
  • Actionable alterations detected in 55% of cisplatin-resistant GCTs, including KIT mutations (enriched in SEM, 29.6%), KRAS mutations (15%), PI3K pathway alterations (13.3%), and MDM2 amplifications (7.6%). PMID:27646943
  • Mean MSK-IMPACT mutation rate of 0.9/Mb confirms that GCTs are among the least mutationally burdened adult solid tumors; 12p gain present in 74% of discovery tumors, consistent with the well-characterized GCT cytogenetic signature. PMID:27646943

Sources

  • cBioPortal study ID: gct_msk_2016
  • DOI: 10.1200/JCO.2016.68.7798
  • Reference genome: hg19

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