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Microsatellite Instability of Germ Cell Tumors Is Associated with Resistance to Systemic Treatment¹

Pathology/Laboratory for Exp. Patho-Oncology [F. M., A. J. M. G., J. W. O., L. H. J. L.] and Pathology/Molecular Diagnostics [W. D.], University Hospital Rotterdam/Daniel, Josephine Nefkens Institute, 3000 DR Rotterdam, the Netherlands, and Department of Oncology, Hematology, Immunology, and Rheumatology, University of Tuebingen Medical Center, Tuebingen 72076, Germany [F. M., C. B.]

Systemic cisplatin-based chemotherapy cures 90% of patients with metastatic germ celltumors (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 2 of 8 loci, both P 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.

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