Microsatellite instability of germ cell tumors is associated with resistance to systemic treatment

Frank Mayer; Ad J M Gillis; Winand Dinjens; J Wolter Oosterhuis; Carsten Bokemeyer; Leendert H J Looijenga

Microsatellite instability of germ cell tumors is associated with resistance to systemic treatment

Frank Mayer
, Ad J M Gillis
, Winand Dinjens
, J Wolter Oosterhuis
, Carsten Bokemeyer
, Leendert H J Looijenga

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2758-60
Number of pages	3
Journal	Cancer Research
Volume	62
Issue number	10
Publication status	Published - 15 May 2002
Externally published	Yes

Keywords

Adaptor Proteins, Signal Transducing
Adolescent
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Carrier Proteins
Cisplatin/administration & dosage
DNA, Neoplasm/genetics
DNA-Binding Proteins/metabolism
Disease-Free Survival
Drug Resistance, Neoplasm
Germinoma/drug therapy
Humans
Immunohistochemistry
Male
Microsatellite Repeats/genetics
Middle Aged
MutL Protein Homolog 1
MutS Homolog 2 Protein
Neoplasm Proteins/metabolism
Nuclear Proteins
Proto-Oncogene Proteins/metabolism
Seminoma/drug therapy
Testicular Neoplasms/drug therapy

Cite this

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title = "Microsatellite instability of germ cell tumors is associated with resistance to systemic treatment",

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-na{\"i}ve (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.",

keywords = "Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Carrier Proteins, Cisplatin/administration \& dosage, DNA, Neoplasm/genetics, DNA-Binding Proteins/metabolism, Disease-Free Survival, Drug Resistance, Neoplasm, Germinoma/drug therapy, Humans, Immunohistochemistry, Male, Microsatellite Repeats/genetics, Middle Aged, MutL Protein Homolog 1, MutS Homolog 2 Protein, Neoplasm Proteins/metabolism, Nuclear Proteins, Proto-Oncogene Proteins/metabolism, Seminoma/drug therapy, Testicular Neoplasms/drug therapy",

author = "Frank Mayer and Gillis, \{Ad J M\} and Winand Dinjens and Oosterhuis, \{J Wolter\} and Carsten Bokemeyer and Looijenga, \{Leendert H J\}",

year = "2002",

month = may,

day = "15",

language = "English",

volume = "62",

pages = "2758--60",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "10",

}

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 -

Microsatellite instability of germ cell tumors is associated with resistance to systemic treatment

Abstract

Keywords

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