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Polymorphisms of multiple genes involved in NER pathway predict prognosis of gastric cancer.

ABSTRACT: Nucleotide excision repair (NER) is a versatile system that repairs various DNA damage. Polymorphisms of core NER genes could change NER ability and affect gastric cancer (GC) prognosis. We systematically analyzed the association between 43 SNPs of ten key NER pathway genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, XPA, XPC, and DDB2) and overall survival (OS) of 373 GC patients in Chinese. Genotyping was performed by Sequenom MassARRAY platform. We found for the first time that carriers of ERCC2 rs50871 GG genotype demonstrated significantly increased hazards of death than GT/TT individuals (HR=2.55, P=0.002); ERCC6 rs1917799 heterozygote GT were associated with significantly shorter OS than wild-type TT (adjusted HR=1.68, P=0.048); patients with DDB2 rs3781619 GG genotype suffered higher hazards of death compared with AG/AA carriers (adjusted HR=2.30, P=0.003). Patients with ERCC1 rs3212961 AA/AC genotype exhibited longer OS than CC genotype (adjusted HR=0.63, P=0.028); ERCC5 rs2094258 AA/AG genotype revealed significantly favorable OS compared with GG genotype (adjusted HR=0.65, P=0.033); DDB2 rs830083 CG genotype could increase OS compared with GG genotype (adjusted HR=0.61, P=0.042). Furthermore, patients simultaneously carrying two "hazard" genotypes exhibited even significantly worse survival with HR of 3.75, 3.76 and 6.30, respectively. Similarly, combination of "favorable" genotypes predicted better prognosis with HR of 0.56, 0.49 and 0.33, respectively. In conclusion, ERCC2 rs50871 G/T, ERCC6 rs1917799 G/T, DDB2 rs3781619 A/G polymorphisms could predict shorter OS while ERCC1 rs3212961 A/C, ERCC5 rs2094258 A/G, DDB2 rs830083 C/G polymorphisms could predict longer OS of GC, which might serve as promising biomarkers for GC prognosis.

SUBMITTER: Liu J

PROVIDER: S-EPMC5217006 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Polymorphisms of multiple genes involved in NER pathway predict prognosis of gastric cancer.

Liu Jingwei J Deng Na N Xu Qian Q Sun Liping L Tu Huakang H Wang Zhenning Z Xing Chengzhong C Yuan Yuan Y

Oncotarget 20160701 30

Nucleotide excision repair (NER) is a versatile system that repairs various DNA damage. Polymorphisms of core NER genes could change NER ability and affect gastric cancer (GC) prognosis. We systematically analyzed the association between 43 SNPs of ten key NER pathway genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, XPA, XPC, and DDB2) and overall survival (OS) of 373 GC patients in Chinese. Genotyping was performed by Sequenom MassARRAY platform. We found for the first time that carriers ...[more]

PMID: 27340861

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Project description:Gastric cancer (GC) is a highly molecular heterogeneous tumor with unfavorable outcomes. The Notch signaling pathway is an important regulator of immune cell differentiation and has been associated with autoimmune disorders, the development of tumors, and immunomodulation caused by tumors. In this study, by developing a gene signature based on genes relevant to the Notch pathway, we could improve our ability to predict the outcome of patients with GC. From the TCGA database, RNA sequencing data of GC tumors and associated normal tissues were obtained. Microarray data were collected from GEO datasets. The Molecular Signature Database (MSigDB) was accessed in order to retrieve sets of human Notch pathway-related genes (NPRGs). The LASSO analysis performed on the TCGA cohort was used to generate a multigene signature based on prognostic NPRGs. In order to validate the gene signature, the GEO cohort was utilized. Using the CIBERSORT method, we were able to determine the amounts of immune cell infiltration in the GC. In this study, a total of 21 differentially expressed NPRGs were obtained between GC specimens and nontumor specimens. The construction of a prognostic prediction model for patients with GC involved the identification and selection of three different NPRGs. According to the appropriate cutoff value, the patients with GC were divided into two groups: those with a low risk and those with a high risk. The time-dependent ROC curves demonstrated that the new model had satisfactory performance when it came to prognostic prediction. Multivariate assays confirmed that the risk score was an independent marker that may be used to predict the outcome of GC. In addition, the generated nomogram demonstrated a high level of predictive usefulness. Moreover, the scores of immunological infiltration of the majority of immune cells were distinctly different between the two groups, and the low-risk group responded to immunotherapy in a significantly greater degree. According to the results of a functional enrichment study of candidate genes, there are multiple pathways and processes associated with cancer. Taken together, a new gene model associated with the Notch pathway may be utilized for the purpose of predicting the prognosis of GC. One potential method of treatment for GC is to focus on NPRGs.

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Polymorphisms of multiple genes involved in NER pathway predict prognosis of gastric cancer.

Publications

Polymorphisms of multiple genes involved in NER pathway predict prognosis of gastric cancer.

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