<i>CYP2A6</i> Polymorphisms Associate with Outcomes of S-1 Plus Oxaliplatin Chemotherapy in Chinese Gastric Cancer Patients

Yang, Lin; Zou, Sheng; Shu, Chen; Song, Yan; Sun, Yongkun; Zhang, Wen; Zhou, Aiping; Yuan, Xinghua; Yang, Yi; Hu, Songnian

doi:10.1016/j.gpb.2016.11.004

Cited by 12 publications

(12 citation statements)

References 32 publications

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“…CYP2A6 is associated with the efficacy of SOX (S-1 plus oxaliplatin) regimen [40], and CYP4F2 partakes in the metabolism of gemcitabine [41]. with a high degree of heterogeneity [17,18].…”

Section: Discussionmentioning

confidence: 99%

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

Wang

Zhang

et al. 2020

Preprint

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Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and its mortality continues to rise globally. Because of its high heterogeneity and complex molecular landscapes, published gene signatures have demonstrated low specificity and robustness. Functional signatures containing a group of genes involved in similar biological functions may display a more robust performance. Methods: The present study was designed to excavate potential functional signatures for PDAC by analyzing maximal number of datasets extracted from available databases with a recently developed method of FAIME (Functional Analysis of Individual Microarray Expression) in a comprehensive and integrated way. Results: Eleven PDAC datasets were extracted from GEO, ICGC and TCGA databases. By systemically analyzing these datasets, we identified a robust functional signature of subpathway (path:00982_1), which belongs to the drug metabolism-cytochrome P450 pathway. The signature has displayed a more powerful and robust capacity in predicting prognosis, drug response and chemotherapeutic efficacy for PDAC, particularly for the classical subtype, in comparison with published gene signatures and clinically used TNM staging system. This signature was verified by meta-analyses and validated in available cell line and clinical datasets with chemotherapeutic efficacy. Conclusion: The present study has identified a novel functional signature for PDAC and it is like to improve the current systems for predicting the prognosis and monitoring drug response, and to serve a potential linkage to therapeutic options for combating PDAC. However, the involvement of path:00982_1 subpathway in the metabolism of anti-PDAC chemotherapeutic drugs, particularly its biological interpretation, requires a further investigation.

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“…CYP2A6 is associated with the efficacy of SOX (S-1 plus oxaliplatin) regimen [40], and CYP4F2 partakes in the metabolism of gemcitabine [41]. with a high degree of heterogeneity [17,18].…”

Section: Discussionmentioning

confidence: 99%

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

Wang

Zhang

et al. 2020

Preprint

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“…Because that the path: 00982_1 subpathway is composed of four groups of enzymes ( Supplementary Table S2) [25], we further studied these enzymes and tried to seek the association with the above chemotherapeutic drugs. CYP2A6 participates in the metabolism of fluorouracil and CYP3A4 is involved with irinotecan pharmacokinetics [39], CYP2A6 is associated with the efficacy of SOX (S-1 plus oxaliplatin) regimen [40], and CYP4F2 partakes in the metabolism of gemcitabine [41]. However, majority of molecules in this subpathway are unable individually to exhibit a significant predictive ability (Analytical Data File 7) by using a univariate Cox method to evaluate the correlation between each gene and the survival of PDAC patients.…”

Section: Discussionmentioning

confidence: 99%

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

Wang

Zhang

et al. 2020

Cell Commun Signal

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Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy and its mortality continues to rise globally. Because of its high heterogeneity and complex molecular landscapes, published gene signatures have demonstrated low specificity and robustness. Functional signatures containing a group of genes involved in similar biological functions may display a more robust performance. Methods: The present study was designed to excavate potential functional signatures for PDAC by analyzing maximal number of datasets extracted from available databases with a recently developed method of FAIME (Functional Analysis of Individual Microarray Expression) in a comprehensive and integrated way. Results: Eleven PDAC datasets were extracted from GEO, ICGC and TCGA databases. By systemically analyzing these datasets, we identified a robust functional signature of subpathway (path:00982_1), which belongs to the drug metabolism-cytochrome P450 pathway. The signature has displayed a more powerful and robust capacity in predicting prognosis, drug response and chemotherapeutic efficacy for PDAC, particularly for the classical subtype, in comparison with published gene signatures and clinically used TNM staging system. This signature was verified by meta-analyses and validated in available cell line and clinical datasets with chemotherapeutic efficacy. Conclusion: The present study has identified a novel functional PDAC signature, which has the potential to improve the current systems for predicting the prognosis and monitoring drug response, and to serve a linkage to therapeutic options for combating PDAC. However, the involvement of path:00982_1 subpathway in the metabolism of anti-PDAC chemotherapeutic drugs, particularly its biological interpretation, requires a further investigation.

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“…This enzyme is encoded by a highly polymorphic gene with over 50 SNPs, some of which reduce or abolish its activity. These genetic variations affect tumor sensitivity to 5-FU and, hence, shorten the survival rates of treated patients [37][38][39][40].…”

Section: Mechanisms Of Chemoresistance Type 2 (Moc-2)mentioning

confidence: 99%

Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma

Marin

Perez‐Silva

Macı́as

et al. 2020

Cancers

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Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer, the fifth according to the frequency and the third among the deadliest cancers. GAC high mortality is due to a combination of factors, such as silent evolution, late clinical presentation, underlying genetic heterogeneity, and effective mechanisms of chemoresistance (MOCs) that make the available antitumor drugs scarcely useful. MOCs include reduced drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), low proportion of active agents in tumor cells due to impaired pro-drug activation or active drug inactivation (MOC-2), changes in molecular targets sensitive to anticancer drugs (MOC-3), enhanced ability of cancer cells to repair drug-induced DNA damage (MOC-4), decreased function of pro-apoptotic factors versus up-regulation of anti-apoptotic genes (MOC-5), changes in tumor cell microenvironment altering the response to anticancer agents (MOC-6), and phenotypic transformations, including epithelial-mesenchymal transition (EMT) and the appearance of stemness characteristics (MOC-7). This review summarizes updated information regarding the molecular bases accounting for these mechanisms and their impact on the lack of clinical response to the pharmacological treatment currently used in GAC. This knowledge is required to identify novel biomarkers to predict treatment failure and druggable targets, and to develop sensitizing strategies to overcome drug refractoriness in GAC.

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CYP2A6 Polymorphisms Associate with Outcomes of S-1 Plus Oxaliplatin Chemotherapy in Chinese Gastric Cancer Patients

Cited by 12 publications

References 32 publications

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

Identification of a robust functional subpathway signature for pancreatic ductal adenocarcinoma by comprehensive and integrated analyses

Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma

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