A molecular cytogenetic approach to studying platinum resistance

The technique of comparative genomic hybridisation (CGH) has until recently been used to screen for common genomic abnormalities in fresh tumour mater ial; it has identified previously unrecognised regions of amplification ass ociated with poor prognosis subtypes of breast cancer and lymphoma. Our gro up has applied this technique to resistant cell lines and their sensitive c ounterparts in order to define chromosomal abnormalities associated with ac quired drug resistance. We have demonstrated the applicability of this tech nique to the study of drug resistance using cell lines with known mechanism s of resistance. The ability to detect novel genomic alterations in cell li nes with novel mechanisms of resistance was also demonstrated. We subsequen tly examined the CGH profiles of seven different cell lines made resistant to three platinum analogues and showed the most consistent abnormalities to involve over-representation of regions 4q and 6q. More recently, we have a pplied the CGH technique to a series of testicular germ cell tumours (TGCTs ) collected as formalin-fixed paraffin-embedded biopsy specimens from patie nts, both pre- and post-therapy using a platinum-based regimen (POMB/ACE). Previous reports have shown over-representation of X, 7q, 8q and 12p and lo ss of 13q to occur in 25% of primary TGCTs. Over-representation of 12p was confirmed in the majority of these biopsy samples; deletion of 13q was note d in the initial biopsies of several patients. We also demonstrated alterat ions of 4p, 4q, 5q and 6q in this series of patients. Newly acquired deleti ons of 2q and 18q and amplifications of 8q were frequently observed in post -chemotherapy samples from resistant tumours. The CGH studies on these pati ents with TGCT will not only enable us to correlate our observations on cli nical material with those from long-term cell lines, but should also identi fy sites of key genes involved in clinical platinum resistance. (C)1999 Els evier Science Inc. All rights reserved.