Array-Based Comparative Genomic Hybridization (Cgh) Identifies Chromosomal Imbalances Between Interleukin-2 Complete And Non-Responders

5043 Background: IL-2 is the only FDA approved treatment for metastatic renal cell cancer capable of producing durable complete responses (CR). However, it is associated with toxicity and a low CR rate. We used array-based CGH to detect a chromosomal profile that distinguishes between IL-2 responders and non-responders. Methods: 10-μm paraffin-embedded tumour sections were cut from 16 RCC patients (5 CRs and 11 Non-Responders (NRs)), tumor areas with >90% clear cell RCC were microdissected, and DNA extracted using phenol/chloroform. Labeled tumor and reference DNAs were applied to Human array 2.0 CGH arrays in triplicate. Fluorescence images were collected using a CCD camera, and analyzed with Spot 2.0 software. For each clone, an average single log2 ratio of test over reference intensity was calculated from replicate spots. The frequency of gains and losses for a given clone was calculated as the proportion of samples in which a clone was gained or lost in that group. Clones with significantly different copy number between different groups were compared using Fisher’s Exact Test. Results: CRs showed fewer whole chromosome changes, more genomic gains, and fewer genomic losses than NRs, who were distinguished by loss of chromosomes 4, 9, and 17p. Of CRs, there was 0% loss of 9p clones, compared to 65% of NRs and 90% of lymph node positive NRs (p<0.001). On 9p, frequently involved regions of loss in NR subjects included 9p13, 9p21, and 9p24 on which CAIX, p16 and S6, and B7H1 genes are located, respectively. In a separate analysis of 282 RCC patients using standard cytogenetics, loss of 4p and 9p were associated with worse survival, and 3 IL-2 responders analyzed had no loss on either 4p or 9p. Conclusions: Patterns of chromosomal imbalance are significantly different in IL-2 Complete and Non-Responders. Loss of chromosome 4, 9, and 17p may identify alterations that can serve as predictors of IL-2 non-response. Further investigation of genes located on these regions may lead to better understanding of the molecular biology of RCC and IL-2 response. If prospectively validated, CGH analysis of genetic alterations may aid clinicians in targeted selection of appropriate treatment options. Funding: NIH K23CA095151–01; NCI P50CA101942 No significant financial relationships to disclose.