Background The androgen receptor (AR) is an essential gene in prostate cancer pathogenesis and progression. Genetic variation in AR exists, including a polymorphic CAG repeat sequence that is inversely associated with transcriptional activity. Experimental data suggest that heightened AR activity facilitates formation of TMPRSS2:ERG, a gene fusion present in approximately 50 percent of tumors of prostate cancer patients. Methods We undertook a nested case-control study to investigate the hypothesis that shorter CAG repeat length would be associated with prostate cancer risk defined by TMPRSS2:ERG status. The study included 291 men with prostate cancer (147 ERG-positive) and 1,221 cancer-free controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. Results Median CAG repeat length (Interquartile range) among controls was 22 (20–24). Men with shorter CAG repeats had an increased risk of ERG-positive (OR=1.07 per 1 repeat decrease, 95% CI 1.00–1.14), but not ERG-negative prostate cancer (OR=0.99 per 1 repeat decrease, 95% CI 0.93–1.05). Conclusions These data suggest that shorter CAG repeats are specifically associated with development of TMPRSS2:ERG positive prostate cancer. Impact Our results provide supportive evidence that androgen signaling underlies the development of prostate tumors that harbor TMPRSS2:ERG. Moreover, these results suggest that TMPRSS2:ERG may represent a unique molecular subtype of prostate cancer with an etiology distinct from TMPRSS2:ERG negative disease.
Irinotecan induces small ubiquitin-like modifier (SUMO)-1 conjugation to topoisomerase-I, leading to enhanced sensitivity to irinotecan. In this study, we genotyped SUMO1 and UBC9 polymorphisms in 147 non-small-cell lung cancer (NSCLC) treated with irinotecan chemotherapy to investigate the association between genotypes and tumor response rate. Immunohistochemistry for SUMO1 and UBC9 was performed in 42 tumor samples and correlated with genotypes. The UBC9 10920CG genotype was associated with significantly higher response rate than the C/C genotype (81 vs 37%, P=0.0002). This predictive effect on tumor response was also seen in multivariate analysis (odds ratio=8.5, 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 vs 31%, P=0.021). This finding suggests that the UBC9 10920CG genotype enhances sensitivity to irinotecan chemotherapy in advanced NSCLC through upregulation of SUMO1 in tumor cells.
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.
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