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Microsatellite instability, mismatch repair deficiency, and BRAF mutation in treatment-resistant germ cell tumors

Friedemann Honecker1, Hendrik Wermann, Frank Mayer

  • 1Department of Oncology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
|March 18, 2009
PubMed
Abstract

Insights

BRAF V600E mutations and mismatch repair deficiency (MMR) leading to microsatellite instability (MSI) are linked to cisplatin resistance in germ cell tumors (GCTs). This suggests potential new therapeutic targets for treatment-resistant GCTs.

Area of Science:

  • Oncology
  • Genetics
  • Cancer Research

Background:

  • Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are known to be associated with cisplatin resistance in human germ cell tumors (GCTs).
  • BRAF V600E mutations are observed in MSI colorectal cancers, but their role in GCT treatment response remains unclear.

Purpose of the Study:

  • To investigate the role of RAS/RAF pathway mutations, specifically BRAF and KRAS, in the context of cisplatin resistance in GCTs.
  • To determine the correlation between MMR deficiency, MSI, and treatment failure in GCT patients.

Main Methods:

  • Analysis of two GCT cohorts: 100 controls and 35 cisplatin-resistant cases.
  • Immunohistochemistry for MMR proteins and examination of eight microsatellite loci for MSI.
  • Assessment of specific BRAF and KRAS mutations in tumor samples.

Main Results:

  • Resistant GCTs exhibited a significantly higher incidence of MSI (26%) compared to controls (0%).
  • BRAF V600E mutations were found in 26% of resistant tumors versus 1% in controls, strongly correlating with MSI.
  • MMR deficiency (hMLH1, MSH6 loss) and BRAF mutations were significantly associated with cisplatin resistance and treatment failure.

Conclusions:

  • This study establishes a novel correlation between BRAF V600E mutation and cisplatin resistance in nonseminomatous GCTs.
  • The findings confirm the association between MMR deficiency, MSI, and treatment failure in GCTs, highlighting their clinical significance.

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