Abstract 3592: Association of SUMO-1 and UBC9 genotypes with tumor response and toxicity in non-small cell lung cancer patients treated with irinotecan-based chemotherapy

Abstract

Abstract Purpose: As the molecular target of irinotecan, TOP1 is a plausible predictive marker for irinotecan chemotherapy. Recently clinical studies have demonstrated that high TOP1 expression in cancer cells was predictive for benefit from irinotecan chemotherapy. Because sumoylation has been implicated in the regulation of protein stability and activity, TOP1 sumoylation may competitively inhibit TOP1 ubiquitination and degradation and lead to increased sensitivity to irinotecan. Thus, we investigated whether SUMO1 and UBC9 genotypes affect tumor response and toxicities in patients with advanced non-small cell lung cancer (NSCLC) treated with irinotecan and cisplatin (IP) chemotherapy. Experimental design: SUMO1 and UBC9 SNPs were selected based on Japanese Hapmap genotyping data (http://www.hapmap.org) and tagging SNP selection were performed with Tagger program (http://www.broad.mit.edu/mpg/tagger) with linkage disequilibrium bin tagging approach. Genomic DNA was extracted from blood samples and genotyped for SUMO1 −8348A>T, −1901C>G, −150G>A, and UBC9 390C>A, −207G>A, 10920C>G. To clarify the independent effects of those polymorphisms on tumor response and toxicities, well known genotypes such as UGT1A1*6, UGT1A1*28, UGT1A9*22, SLCO1B1 521T>C, ABCC2 −24C>T, ABCC2 3972C>T, ABCG2 34G>A genotypes were also examined and correlated with tumor response and toxicities. Immunohistochemistry for SUMO1 and UBC9 was performed on 42 tumor samples and correlated with genotypes. Results: There were 147 patients included in this analysis, including 115 men and 32 women with a median age of 61 (range, 29 to 77 years). Of 147 patients, 143 were assessable for tumor responses to IP chemotherapy. The overall response rate (ORR) was 43%; 61 had partial responses; 47 had stable diseases; and 35 had progressive diseases. Among SUMO1 and UBC9 polymorphisms examined, only the UBC9 10920C>G was associated with tumor responses. Patients with the UBC9 10920CG genotype had a significantly higher ORR than those with homozygous CC (81% v 37%, P = 0.0002). In a multivariate logistic analysis using the associated factors with P<0.1 as predictive variables, only the UBC9 10920CG variant maintained its predictive value on tumor response to IP chemotherapy (OR =8.5, 95% CI; 2.1 to 34.6, P=0.003). Moreover, tumors arising from the UBC9 10920CG genotype were associated with higher prevalence of SUMO1 overexpression compared with those with CC genotype (78% v 31%, P=0.021). However, none of SUMO1 and UBC9 polymorphisms was significantly predictive for irinotecan-related severe toxicities. Conclusions: This finding suggests that the UBC9 10920CG genotype enhances sensitivity to irinotecan chemotherapy in advanced NSCLC through upregulation of SUMO1 in tumor cells (This study was supported by a grant from National Cancer Center 0810130-2). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3592.