Resistance of Human Male Germ Cell Tumors Chromosomal Amplification Is Associated with Cisplatin

Chemotherapy resistance of tumors is an important biological and clinical problem. Studies Troni many tumor types have indicated that resistance may he hased on multiple genetic pathways. Human male (¡ermacell tumors (GCTs) are an especially good model system to study the genetic hasis of tumor sensitivity and resistance to chemotherapy. GCTs are exquisitely sensitive to treatment with DNA-damaging drugs such as cisplatin. rarely exhihit / /'5 <gene mutations, express normal p53 protein, and undergo p53-mcdiatcd apoptosis upon drug treatment. A small proportion of tumors (20-30% of metastatic lesions) escape the apoptotic response and result in treatment resistance. We have recently shown (J. Houldsworth, et al.. Oncogene. 16: 2345-2359. 1998) that in a suhset of such tumors, resistance is linked to TP53 gene mutations. In a further search for genetic mechanisms underlying resistance, we subjected a panel of 17 tumors from relapse-free patients (sensitive) and 17 chemo therapy-resistant tumors to comparative genomic hybridization analysis to identify possible amplified regions (implying amplified/overexpressed genes) associated with resistance. With the exception of 12pl 1.2-12, high level amplification was not detected in any of the sensitive tumors. We have identified eight amplified regions (lq31-32, 2p23-24, 7q21, 7q31, 9q22. 9q32-34, 15q23-24. and 20ql 1.2-12) in five resistant tumors, which suggests that chromosomal and. hence, gene amplification may comprise a pathway to drug resistance. Identification of amplified/overexpressed genes at these sites may elucidate new genetic pathways of chemotherapy resistance in GCTs and possibly also in other tumors.