Advances in Brief Microsatellite Instability of Germ Cell Tumors Is Associated with Resistance to Systemic Treatment 1

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.

[1]  C. Bokemeyer,et al.  Role of P53 and MDM2 in treatment response of human germ cell tumors. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  F. Berger,et al.  Expression of hMLH1 and hMSH2 and assessment of microsatellite instability in testicular and mediastinal germ cell tumours. , 2001, Molecular human reproduction.

[3]  H. Hemmi,et al.  A change in microsatellite instability caused by cisplatin-based chemotherapy of ovarian cancer , 2001, British Journal of Cancer.

[4]  D. Watson,et al.  Defects of DNA mismatch repair in human prostate cancer. , 2001, Cancer research.

[5]  J. Barrett,et al.  Involvement of mammalian MLH1 in the apoptotic response to peroxide-induced oxidative stress. , 2001, Cancer research.

[6]  J. G. Park,et al.  Microsatellite instability is associated with genetic alteration but not with low levels of expression of the human mismatch repair proteins hMSH2 and hMLH1. , 2000, European journal of cancer.

[7]  S. Thibodeau,et al.  HMSH6 alterations in patients with microsatellite instability-low colorectal cancer. , 2000, Cancer research.

[8]  M. Morris,et al.  High‐dose chemotherapy as primary treatment for poor‐risk germ‐cell tumors: The Memorial Sloan‐Kettering experience (1988–1999) , 1999, International journal of cancer.

[9]  A. Millar,et al.  Immunohistochemistry for hMLH1 and hMSH2: a practical test for DNA mismatch repair-deficient tumors. , 1999, The American journal of surgical pathology.

[10]  L. Messerini,et al.  Prognostic significance of microsatellite instability in sporadic mucinous colorectal cancers. , 1999, Human pathology.

[11]  L. Looijenga,et al.  Heterogeneous X inactivation in trophoblastic cells of human full-term female placentas. , 1999, American journal of human genetics.

[12]  N. Claij,et al.  Microsatellite instability in human cancer: a prognostic marker for chemotherapy? , 1999, Experimental cell research.

[13]  S Srivastava,et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. , 1998, Cancer research.

[14]  V. Reuter,et al.  Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation , 1998, Oncogene.

[15]  C. Macleod,et al.  In vitro and in vivo resistance to cisplatin in cells that have lost DNA mismatch repair. , 1997, Cancer research.

[16]  C. Boland,et al.  Loss of DNA mismatch repair in acquired resistance to cisplatin. , 1996, Cancer research.

[17]  R. Lothe,et al.  Molecular genetic changes in human male germ cell tumors. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[18]  H. Adami,et al.  Testicular cancer in nine northern european countries , 1994, International journal of cancer.

[19]  V. Reuter,et al.  Replication error-type genetic instability at 1q42-43 in human male germ cell tumors. , 1994, Cancer research.

[20]  L. Aaltonen,et al.  Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. , 1993, Cancer research.

[21]  M. Dietel,et al.  Involvement of the DNA mismatch repair system in antineoplastic drug resistance , 1999, Journal of Cancer Research and Clinical Oncology.

[22]  I. Sesterhenn,et al.  Histological Typing of Testis Tumours , 1998, World Health Organization.