Germ Cell Tumor (GCT)

Overview

Germ Cell Tumor is an umbrella OncoTree designation for testicular and extragonadal germ cell tumors. Note: in the OncoTree hierarchy, GCT canonically maps to “Granular Cell Tumor” in the Sellar Tumor branch; within the cBioPortal study gct_msk_2016 the code is used specifically for testicular and mediastinal germ cell tumors. The corpus usage refers to NSGCT (non-seminomatous GCT) and SEM (seminoma) as the principal histologic subtypes, with primary sites including testis (TT), mediastinum, and retroperitoneum.

Cohorts in the corpus

  • gct_msk_2016 — N=180 men with advanced GCT receiving first-line cisplatin-based chemotherapy at Memorial Sloan Kettering Cancer Center; 19 tumors by whole-exome sequencing (discovery) + 161 by MSK-IMPACT targeted sequencing (validation); 76 cisplatin-sensitive vs 104 resistant PMID:27646943.

Recurrent alterations

  • 12p gain — present in 74% of discovery tumors; the well-characterized GCT cytogenetic hallmark PMID:27646943.
  • TP53 — alterations exclusive to cisplatin-resistant tumors (17/104 [16.3%] resistant vs 0/76 sensitive, P<.001); 72% of primary mediastinal nonseminomas harbored TP53 alterations; strongest single-gene biomarker of cisplatin resistance PMID:27646943.
  • MDM2 — amplifications in 7.6% of resistant vs 2.6% sensitive tumors; mutually exclusive with TP53 alteration; combined TP53/MDM2 alterations in 24.0% of resistant vs 2.6% sensitive (P<.001) PMID:27646943.
  • MYCN — amplifications in 5 patients, all cisplatin resistant; transcriptionally targets both TP53 and MDM2 PMID:27646943.
  • RAC1 — novel hotspot mutations at codons 12, 34, 61 (G12V/R, P34R, Q61R/K) in 9 patients (5% — highest reported across TCGA cancer types at time of publication); functionally validated to activate PAK1 and MEK1/2 phosphorylation PMID:27646943.
  • KIT — exon 17 hotspot mutations in 19 patients; enriched in SEM (29.6% vs 4% in nonseminoma, P<.001) PMID:27646943.
  • KRAS — 22 patients (G12 dominant); enriched in seminomas overall (20% vs 8.7%, P=.045) PMID:27646943.
  • PI3K pathway — alterations in 13.3% (PIK3CA E542K ×4, PTEN LOF ×5, AKT1 amplification, MTOR, TSC1, TSC2) PMID:27646943.
  • Mean MSK-IMPACT mutation rate of 0.9/Mb — very low compared with other adult solid tumors PMID:27646943.

Subtypes

  • NSGCT — non-seminomatous GCT; 70% of the cohort (n=126); lower KIT mutation rate (4%) than seminoma; KRAS mutations in nonseminomas enriched in cisplatin-resistant tumors PMID:27646943.
  • SEM — seminoma; 30% of cohort (n=54); high KIT mutation rate (29.6%); enriched KRAS PMID:27646943.
  • MGCT — mixed GCT (teratoma-containing); 49 resistant samples PMID:27646943.
  • Primary mediastinal nonseminoma — uniquely poor prognosis; 72% TP53 alteration rate vs 2.5% in testicular primaries (P<.001); provides molecular basis for IGCCCG poor-risk designation PMID:27646943.

Therapeutic landscape

  • Cisplatin-based chemotherapy (BEP/EP/TIP/VIP) — standard first-line; cisplatin resistance is the central clinical challenge; TP53/MDM2 alterations independently predict shorter PFS (HR 1.83, P=.016) after adjusting for IGCCCG risk PMID:27646943.
  • Nutlin-3 (MDM2 inhibitor) — showed antiproliferative and apoptotic synergy with cisplatin in TP53 wild-type cisplatin-resistant cell lines in vitro; 7 MDM2 inhibitors in clinical trials at time of publication PMID:27646943.
  • Imatinib/sunitinib — therapeutic candidates for KIT-mutant GCT (particularly seminoma) PMID:27646943.
  • MEK inhibitors (trametinib, selumetinib, binimetinib) — candidates for KRAS/NRAS/RAC1-altered GCT PMID:27646943.

Sources

  • PMID:27646943 — Bagrodia et al. 2016 (JCO). Whole-exome + MSK-IMPACT sequencing of 180 advanced GCT; TP53/MDM2 alterations exclusive to cisplatin-resistant tumors; novel RAC1 hotspot mutations.

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