Mismatch repair gene expression and genetic instability in testicular germ cell tumor

Cancer Biol Ther. 2004 Oct;3(10):977-82. doi: 10.4161/cbt.3.10.1135. Epub 2004 Oct 2.


Human mismatch repair (MMR) genes encode highly conserved interacting proteins that correct replication errors predisposing to hereditary gastrointestinal and genitourinary malignancies. A subset of sporadic genitourinary tumors also exhibits MMR deficiency and can be identified by measuring the frequency of microsatellite instability (MSI) in cancer cell DNA. We investigated expression of the two most commonly mutated MMR genes, MSH2 and MLH1, in sporadic testicular germ cell tumor (GCT) in order to: (1) determine the expression pattern of MSH2 and MLH1 proteins in normal seminiferous tubules and histologically distinct GCT subtypes, (2) correlate MMR gene expression with genetic instability in GCT and (3) develop a panel of molecular markers that can identify genetically distinct subsets of GCT for prognostic assessment. MSH2 and MLH1 had differential staining patterns in normal seminiferous tubules and malignant tissues. MSH2 was expressed in all stages of spermatogenesis up to but excluding mature sperm whereas MLH1 was predominantly expressed in premeiotic germ cells. All histological GCT subtypes showed differential immunostaining for MSH2 and MLH1 however pure seminoma had statistically significant fewer low MSH2 staining tumors than other subtypes (p = 0.046). Twenty-five percent of GCT exhibited increased frequency of MSI (MSI+ tumors) with 73, 70 and 43% of MSI+ tumors exhibiting low MSH2, low MLH1 or low MSH2 and low MLH1 staining respectively. Fifteen percent of testicular GCT exhibited loss of heterozygosity (LOH) but no MSI (LOH only tumors). Only 28, 17 or 6% of LOH only tumors exhibited low MSH2, low MLH1 or low MSH2 and low MLH1 staining respectively.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Base Pair Mismatch / genetics*
  • Carrier Proteins
  • Chromosomal Instability*
  • DNA Repair / genetics*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Loss of Heterozygosity
  • Male
  • Microsatellite Repeats
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Neoplasms, Germ Cell and Embryonal / genetics
  • Neoplasms, Germ Cell and Embryonal / metabolism
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prognosis
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Seminiferous Tubules / metabolism
  • Seminiferous Tubules / pathology
  • Testicular Neoplasms / genetics*
  • Testicular Neoplasms / metabolism


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein