The exceptional sensitivity of
germ cell tumors (GCTs) of adolescents and adults to
chemotherapy, in particular to
cisplatin, has been attributed to low levels of
xeroderma pigmentosum group A protein (XPA), a crucial component of the nucleotide excision repair DNA repair pathway. In different types of solid
tumors, resistance to
cisplatin has been associated with enhanced expression of XPA. To assess the role of XPA levels in clinical sensitivity and resistance of GCTs to
chemotherapy, immunohistochemistry was performed on
tumor samples of both unselected patients before
therapy and patients with fully documented
clinical course before and after
therapy. In the case of high XPA levels, fluorescent in situ hybridization was applied to assess the possibility of gene amplification. XPA
protein levels were investigated by Western blot analysis after repeated exposure to
cisplatin in different GCT-derived cell lines. Finally, XPA levels of both sensitive and
cisplatin-resistant GCT cell lines were compared with cell lines derived from other
neoplasms. We found that the presence of XPA
protein as assessed by immunohistochemistry differs among the various histologies of GCTs. It is found more frequently and with a more homogenous staining pattern in histologic subtypes showing a more differentiated phenotype. Overall, no differences in the presence of XPA was observed between samples of
tumors refractory or sensitive to
chemotherapy. No XPA gene amplification was found. Interestingly, all
tumors resected in relapse after
chemotherapy in the refractory group stained positive for XPA. However, XPA was not induced by repeated courses of sublethal doses of
cisplatin in GCT-derived cell lines in vitro, and no correlation between XPA
protein levels and sensitivity to
cisplatin in three GCT-derived cell lines was observed. We therefore conclude that XPA does not play a critical role in overall treatment resistance of GCTs.