Non-Seminomatous Germ Cell Tumor (NSGCT)

Overview

Non-Seminomatous Germ Cell Tumor encompasses testicular germ cell tumors with non-seminomatous histology (embryonal carcinoma, yolk sac tumor, choriocarcinoma, and teratoma elements), sitting under TESTIS in OncoTree. NSGCT carries distinct molecular features versus seminoma, including a lower KIT mutation frequency and greater tendency for TP53 alterations in cisplatin-resistant disease.

Cohorts in the corpus

  • gct_msk_2016 — 126 NSGCT patients (70% of the 180-patient MSK GCT cohort); profiled by whole-exome sequencing (discovery, n=19) and MSK-IMPACT targeted sequencing (validation, n=161) PMID:27646943.

Recurrent alterations

  • TP53 — alterations exclusive to cisplatin-resistant tumors in the combined cohort; particularly enriched in primary mediastinal nonseminomas (72.2% of 18 primary mediastinal NSGCT vs 2.5% in testicular primaries, P<.001) PMID:27646943.
  • KIT — mutations in only 4% of nonseminomas versus 29.6% in seminomas (P<.001); predominantly exon 17 hotspots PMID:27646943.
  • KRAS — mutations in 8.7% of nonseminomas; in nonseminomas, 8 of 11 KRAS mutations occurred in cisplatin-resistant tumors PMID:27646943.
  • RAC1 — novel hotspot mutations (G12V/R, P34R, Q61R/K) at 5% frequency; functionally validated to activate PAK1 and MEK1/2 PMID:27646943.
  • MDM2 — amplifications in cisplatin-resistant NSGCT; mutually exclusive with TP53 alterations PMID:27646943.
  • PI3K pathway — PIK3CA, PTEN, AKT1, MTOR, TSC1, TSC2 alterations in ~13% of combined cohort PMID:27646943.

Subtypes

  • Primary mediastinal nonseminoma — extreme poor prognosis subgroup; 72% TP53 alteration rate provides molecular basis for its IGCCCG designation as a special-risk category independent of stage PMID:27646943.
  • MGCT — mixed GCT containing teratoma elements; 49 of the resistant NSGCT samples were MGCT PMID:27646943.

Therapeutic landscape

  • Cisplatin-based chemotherapy (BEP/EP/TIP) — standard first-line; TP53/MDM2 alterations independently predict shorter PFS (HR 1.83, 95% CI 1.12–2.98, P=.016) beyond IGCCCG risk model PMID:27646943.
  • MEK inhibitors — therapeutic candidates for KRAS/NRAS/RAC1-altered cisplatin-resistant NSGCT PMID:27646943.
  • PI3K/mTOR inhibitors — for PI3K-pathway-altered tumors; PARP inhibitors for BRCA2 deletion PMID:27646943.

Sources

  • PMID:27646943 — Bagrodia et al. 2016 (JCO). 126 NSGCT in MSK cohort of 180 advanced GCT; TP53 exclusive to cisplatin resistance; 72% TP53 in primary mediastinal nonseminoma.

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