title: Xeroderma pigmentosum group a protein and chemotherapy resistance in human germ cell tumors.
abstract: 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.
authors.affiliation: Department of Pathology, Laboratory for Experimental Patho-Oncology, Josephine Nefkens Institute, Erasmus MC, University Medical Center Rotterdam, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Honecker
authors.forename: Frank
authors.initials: F
authors.lastname: Mayer
authors.forename: Hans
authors.initials: H
authors.lastname: Stoop
authors.forename: J Wolter
authors.initials: JW
authors.lastname: Oosterhuis
authors.forename: Sandra
authors.initials: S
authors.lastname: Koch
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: Leendert H J
authors.initials: LH
authors.lastname: Looijenga
mesh_terms: D000293:Adolescent; D000328:Adult; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D018237:Germinoma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D013736:Testicular Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D014407:Tumor Cells, Cultured; D014983:Xeroderma Pigmentosum; D051760:Xeroderma Pigmentosum Group A Protein
chemical_list: D004268:DNA-Binding Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D002945:Cisplatin