Plasma MRNA As Potential Real-time Chemosensitivity Predictive Biomarkers In Gastric Cancer

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Thymidylate synthase(TS)mRNA levels in plasma and tumor as potential predictive biomarkers for raltitrexed sensitivity in gastric cancerBackground:Different chemotherapeutic agents currently available are effective only in certain subsets of patients.Predictive biomarkers will be helpful in choosing those agents and can improve the clinical efficiency by a more personalized chemotherapeutic approach.Raltitrexed is a novel water-soluble quinazoline folate analogue and can improve the efficiency of gastric cancer treatment,but its predictive biomarker remains unclear.The aim of this study was to investigate the role of plasma and tumor TS mRNA levels as predictive biomarkers for raltitrexed in gastric cancer.Methods:125 freshly-removed gastric tumor specimens and corresponding blood samples before surgery were collected.Raltitrexed sensitivity was determined by histoculture drug response assay(HDRA)procedures.TS mRNA levels in tumor and plasma were determined by quantitative RT-PCR.Results:Plasma TS mRNA level in cancer patients was significantly higher than in healthy subjects(P = 0.009)and was significantly correlated with TS mRNA level in tumor tissues(r=0.665,P<0.001).Tumor and plasma TS mRNA expression levels were significantly lower in raltitrexed-sensitive group than in resistant group(P = 0.007,P = 0.013,respectively).The sensitivity and accuracy of raltitrexed sensitivity prediction based on plasma TS mRNA levels were 82%and 60%,respectively;whereas the prediction based on tumor TS mRNA reached 70%sensitivity and 68%accuracy.Conclusion:These results indicate that TS mRNA level in plasma can mirror tumor TS mRNA level,and both of them can be used to predict raltitrexed sensitivity in gastric cancer.Part ? Plasma mRNA expression levels as potential real-time predictive biomarkers for chemosensitivity in gastric cancerBackground:Personalized chemotherapy based on predictive biomarkers can maximize efficacy.However,tumor tissue obtained at the time of initial diagnosis will not reflect genetic alterations observed at the time of clinical progression.Biomarker from blood could be a useful and non-invasive tool to provide real-time information in the whole procedure of treatment.Methods:In 150 gastric cancer patients,mRNA levels of BRCA1,TS,ERCC1,hENTl,RRM1,Topol and APTX were assessed in plasma and paired formalin-fixed paraffin-embedded tumor tissue and correlated with chemosensitivity to docetaxel,pemetrexed,platinum,gemcitabine and irinotecan.Results:Significant correlations were observed between plasma and tumor mRNA levels of BRCA1,ERCC1,hENTl,RRM1,TS,Topol,and APTX(P<0.001 for all genes).Correlations were also observed between the mRNA expression of plasma/tumor BRCA1 levels and docetaxel sensitivity(P<0.001),plasma/tumor TS and pemetrexed sensitivity(P<0.001),plasma/tumor ERCC1 and platinum sensitivity(plasma,P = 0.012;tumor,P<0.001),plasma/tumor RRM1 and gemcitabine sensitivity(plasma,P = 0.004;tumor,P<0.001),and plasma/tumor Topol and irinotecan sensitivity(plasma,P = 0.015;tumor,P = 0.013).Plasma mRNA levels showed considerable sensitivity and specificity in predicting chemosensitivity(P<0.001).Gastric cancer patients with low levels of plasma ERCC1 mRNA could benefit from platinum-based chemotherapy(546 days vs.355 days,HR:0.31,P = 0.003).Conclusion:Plasma mRNA expression levels mirror those in the tumor and can be used as promising predictive biomarkers to predict chemosensitivity.Part ? Gene signature in plasma and tumor predicts irinotecan chemosensitivity in gastric cancerBackground:Personalized chemotherapy based on molecular biomarkers can maximum efficiency and reduce adverse effects.We investigated and validated predictive biomarkers for irinotecan and developed a three-gene signature that is closely associated with chemosensitivity to irinotecan in gastric cancer patients.Methods:We examined gene expression of APTX,BRCA1,ERCC1,ISG15 and Topol in plasma and paired formalin-fixed paraffin-embedded gastric cancer tissues from 175 patients and evaluated the association between gene expression levels and in vitro sensitivity to irinotecan.We used multiple linear regression analysis to develop a gene-expression model to predict irinotecan sensitivity in gastric cancer and validated this model in vitro and vivo.Results:The tumor gene expression levels of APTX(P<0.001),BRCA1(P<0.001)and ERCC1(P<0.001)were significantly lower in irinotecan-sensitive gastric cancer samples than those irinotecan-resistant samples,while ISG15(P = 0.047)and Topo1(P = 0.002)were significantly higher.The plasma gene expression levels of APTX(P = 0.006)and BRCA1(P = 0.019)were significantly lower in irinotecan-sensitive gastric cancer samples than those irinotecan-resistant samples,while ISG15(P<0.001)and Topo1(P = 0.001)were significantly higher.Based on those genes,plasma and tumor gene signature for irinotecan sensitivity prediction were established,respectively.The tumor gene signature was significantly associated with irinotecan sensitivity(rho = 0.71,P<0.001).The sensitivity and specificity for the prediction of irinotecan sensitivity based on the tumor gene signature reached 73%and 86%,respectively.We also validated the model in another independent set of gastric cancer samples and two cohorts of immunodeficient mice models with patient-derived gastric cancer xenografts.The plasma gene signature was significantly associated with irinotecan sensitivity(rho = 0.642,P<0.001).The sensitivity and specificity for the prediction of irinotecan sensitivity based on the plasma gene signature reached 63%and 87%,respectively.We also validated the model in another independent set of gastric cancer samples(65%vs.22%,P<0.001).Conclusions:The gene signatures established herein based plasma and tumor gene expression levels are closely associated with irinotecan sensitivity among patients with gastric cancer.