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RAS/MAPK Pathway Driver Alterations Are Significantly Associated With Oncogenic KIT Mutations in Germ-cell Tumors

Douglas A Mata1, Soo-Ryum Yang1, Donna C Ferguson1

  • 1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.

Urology
|July 30, 2020
PubMed
Abstract

Insights

Somatic KIT mutations occur in 8.1% of germ cell tumors (GCTs), often co-occurring with RAS/MAPK pathway alterations. Novel therapies targeting KIT or MEK/KIT may benefit patients with chemotherapy-refractory GCTs.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Germ cell tumors (GCTs) are the most common solid malignancy in young men.
  • Activating mutations in KIT, a receptor tyrosine kinase, are found in a subset of GCTs.
  • Understanding the mutational landscape of KIT-mutant GCTs is crucial for developing targeted therapies.

Purpose of the Study:

  • To characterize the mutational profile of KIT-mutant GCTs.
  • To investigate the clinical outcomes of patients with KIT-mutant GCTs.
  • To identify potential therapeutic strategies for KIT-mutant GCTs.

Main Methods:

  • Retrospective cohort study of 568 GCT patients.
  • DNA next-generation sequencing (MSK-IMPACT) to identify somatic mutations.
  • Analysis of clinical outcomes including metastasis and treatment response.

Main Results:

  • 8.1% of GCTs harbored somatic KIT mutations, predominantly in exons 17, 11, and 13.
  • KIT-mutant GCTs showed enrichment for RAS/MAPK pathway alterations (34.8%) compared to KIT-wildtype (19.2%).
  • Nonseminomatous GCTs (NSGCTs) had a significantly higher risk of death than seminomas; no patients received KIT-directed therapies.

Conclusions:

  • Concurrent RAS/MAPK alterations may explain the limited efficacy of prior KIT-directed therapies.
  • Novel KIT-directed tyrosine kinase inhibitors (TKIs) targeting exon 17 mutations could benefit chemotherapy-refractory patients lacking RAS/MAPK alterations.
  • Dual MEK/KIT inhibitor therapy presents a potential strategy for KIT-mutant GCTs with concurrent RAS/MAPK alterations.

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