TY - JOUR
T1 - Microsatellite instability of germ cell tumors is associated with resistance to systemic treatment
AU - Mayer, Frank
AU - Gillis, Ad J M
AU - Dinjens, Winand
AU - Oosterhuis, J Wolter
AU - Bokemeyer, Carsten
AU - Looijenga, Leendert H J
PY - 2002/5/15
Y1 - 2002/5/15
N2 - 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.
AB - 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.
KW - Adaptor Proteins, Signal Transducing
KW - Adolescent
KW - Adult
KW - Aged
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Carrier Proteins
KW - Cisplatin/administration & dosage
KW - DNA, Neoplasm/genetics
KW - DNA-Binding Proteins/metabolism
KW - Disease-Free Survival
KW - Drug Resistance, Neoplasm
KW - Germinoma/drug therapy
KW - Humans
KW - Immunohistochemistry
KW - Male
KW - Microsatellite Repeats/genetics
KW - Middle Aged
KW - MutL Protein Homolog 1
KW - MutS Homolog 2 Protein
KW - Neoplasm Proteins/metabolism
KW - Nuclear Proteins
KW - Proto-Oncogene Proteins/metabolism
KW - Seminoma/drug therapy
KW - Testicular Neoplasms/drug therapy
M3 - Article
C2 - 12019150
SN - 0008-5472
VL - 62
SP - 2758
EP - 2760
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -