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Microsatellite instability of germ cell tumors is associated with resistance to systemic treatment
Frank Mayer1, Ad J M Gillis, Winand Dinjens
1Pathology/Laboratory for Exp. Patho-Oncology, University Hospital Rotterdam/Daniel, Josephine Nefkens Institute, Erasmus University Rotterdam, 3000 DR Rotterdam, the Netherlands.
Abstract:
Systemic cisplatin-based chemotherapy cures > or =90% of patients with metastatic germ cell tumors (GCTs). The biological basis of this exquisite chemo-sensitivity and the resistant phenotype encountered in 10-15% of patients with GCT is yet unclear. A defective mismatch repair pathway leading to microsatellite instability (MSI) has been related to resistance to cytotoxic drugs. We investigated 100 unselected GCTs and 11 clinically defined chemotherapy-resistant GCTs for MSI using 8 mono- or dinucleotide markers and the presence of the mismatch repair factors MLH1, MSH2, and MSH6 by immunohistochemistry. The resistant tumors, both chemo-naïve (n = 8) and pretreated (n = 3), showed a significantly higher incidence of MSI compared with the unselected series (45 versus 6% in at least one locus and 36 versus 0% in > or =2 of 8 loci, both P < or = 0.001). In 5 of all 11 unstable tumors, MSI correlated with immunohistochemical findings. This study demonstrates for the first time a positive correlation between MSI and treatment resistance in GCT.
Insights
Microsatellite instability (MSI) is linked to chemotherapy resistance in germ cell tumors (GCTs). This study found a significant correlation between MSI and treatment resistance in GCT patients, suggesting a potential biomarker for predicting outcomes.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Germ cell tumors (GCTs) are highly sensitive to cisplatin-based chemotherapy, yet 10-15% of patients develop resistance.
- The underlying biological mechanisms of GCT chemo-sensitivity and resistance remain largely unknown.
- Defects in DNA mismatch repair (MMR) pathways, leading to microsatellite instability (MSI), are associated with resistance to cytotoxic drugs.
Purpose of the Study:
- To investigate the prevalence of MSI in GCTs.
- To determine the association between MSI and chemotherapy resistance in GCT patients.
- To explore the correlation between MSI and MMR protein expression in GCTs.
Main Methods:
- Analysis of 100 unselected GCTs and 11 clinically defined chemotherapy-resistant GCTs.
- MSI detection using 8 mono- or dinucleotide markers.
- Immunohistochemical assessment of MMR factors MLH1, MSH2, and MSH6.
Main Results:
- A significantly higher incidence of MSI was observed in resistant GCTs compared to unselected GCTs (45% vs 6% in at least one locus; 36% vs 0% in >=2 of 8 loci; P <= 0.001).
- MSI was detected in both chemo-naïve (8/11) and pretreated (3/11) resistant tumors.
- Correlation between MSI and immunohistochemical findings was noted in 5 of the 11 unstable tumors.
Conclusions:
- This study provides the first evidence of a positive correlation between microsatellite instability and treatment resistance in germ cell tumors.
- MSI may serve as a predictive biomarker for chemotherapy resistance in GCT patients.
- Further research into the role of MMR defects in GCT chemo-resistance is warranted.