Expression and clinical role of chemoresponse-associated genes in ovarian serous carcinoma

• An 11-gene chemoresistance signature highlights heterogeneity in ovarian carcinoma
• APC, MAPK3 and S100A10 are potential biomarkers of poor chemotherapy response in primary serous ovarian carcinoma
• Higher BAG3 and APC mRNA and S100A10 protein expression is associated with poor survival in primary serous ovarian carcinoma

ObjectiveTo validate our earlier observation that 11 chemoresistance-associated mRNAs are molecular markers of poor overall survival in ovarian serous carcinoma.MethodsOvarian serous carcinomas (n = 112) and solid metastases (n = 63; total = 175) were analyzed for mRNA expression of APC, BAG3, EGFR, S100A10, ITGAE, MAPK3, TAP1, BNIP3, MMP9, FASLG and GPX3 using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters and survival. Tumor heterogeneity was assessed in 20 cases with > 1 specimen per patient. APC, BAG3, S100A10 and ERK1 protein expression by immunohistochemistry was analyzed in 58 specimens (38 primary carcinomas, 20 metastases).ResultsBAG3 (p = 0.013), TAP1 (p = 0.014), BNIP3 (p < 0.001) and MMP9 (p = 0.036) were overexpressed in primary tumors, whereas S100A10 (p = 0.027) and FASLG (p = 0.006) were overexpressed in metastases. Analysis of patient-matched primary carcinomas and metastases showed overexpression of APC (p = 0.022), MAPK3 (p = 0.002) and BNIP3 (p = 0.004) in the former. In primary carcinomas, higher APC (p = 0.003) and MAPK3 (p = 0.005) levels were related to less favorable chemoresponse. Higher S100A10 (p = 0.029) and MAPK3 (p = 0.041) levels were related to primary chemoresistance. Higher BAG3 (p = 0.026) and APC (p = 0.046) levels in primary carcinomas were significantly related to poor overall survival in univariate, though not in multivariate survival analysis. S100A10 protein expression was related to poor chemoresponse (p = 0.002) and shorter overall (p = 0.005) and progression-free (p < 0.001) survival, the latter finding retained in multivariate analysis (p = 0.035).ConclusionsOur data provide evidence of heterogeneity in ovarian serous carcinoma and identify APC, MAPK3, BAG3 and S100A10 as potential biomarkers of poor chemotherapy response and/or poor outcome in this cancer.