Dataset Information

Association Between ERCC1 rs3212986 and ERCC2/XPD rs1799793 and OS in Patients With Advanced Esophageal Cancer.

ABSTRACT: Esophageal cancer (EC) is a very aggressive tumor, and no reliable prognostic markers exist especially for resectable advanced neoplasia. The principal aim of this study was to investigate the association of germline polymorphisms in nucleotide excision repair (NER) pathway genes with the overall survival (OS) of patients with advanced EC. As a second aim, we also studied the association of NER gene variants with response to cisplatin-based chemotherapy. Among the EC patients referred to our Institution between 2004 and 2012, we selected a cohort of 180 patients diagnosed with a clinical tumor stage ranging from IIB and IVA. Patients were genotyped for four NER variants, two in the ERCC1 (rs11615 and rs3212986) and two in the ERCC2/XPD (rs1799793 and rs13181) genes. Kaplan-Meier analyses and Cox proportional hazards model were used to evaluate the associations of the selected variants with OS; association with response to neoadjuvant therapy was investigated using logistic regression. Results showed that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 were significantly associated with shorter OS. On the contrary, response association analysis displayed that, while rs11615 and rs3212986 in ERCC1 were associated with response, both ERCC2/XPD variants were not. By creating survival prediction models, we showed that the rs3212986 and the rs1799793 have a better predictability of the tumor stage alone. Furthermore, they were able to improve the power of the clinical model (AUC = 0.660 vs. AUC = 0.548, p = 0.004). In conclusion, our results indicate that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 could be used as surrogate markers for a better stratification of EC patients with advanced resectable tumor.

SUBMITTER: Boldrin E

PROVIDER: S-EPMC6393335 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Association Between <i>ERCC1</i> rs3212986 and <i>ERCC2/XPD</i> rs1799793 and OS in Patients With Advanced Esophageal Cancer.

Boldrin Elisa E Malacrida Sandro S Rumiato Enrica E Battaglia Giorgio G Ruol Alberto A Amadori Alberto A Saggioro Daniela D

Frontiers in oncology 20190221

Esophageal cancer (EC) is a very aggressive tumor, and no reliable prognostic markers exist especially for resectable advanced neoplasia. The principal aim of this study was to investigate the association of germline polymorphisms in nucleotide excision repair (NER) pathway genes with the overall survival (OS) of patients with advanced EC. As a second aim, we also studied the association of NER gene variants with response to cisplatin-based chemotherapy. Among the EC patients referred to our Ins ...[more]

PMID: 30847299

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Project description:ObjectivesTo comprehensively evaluate the association of ERCC1 C8092A and ERCC2 Lys751Gln polymorphisms with the risk of glioma.MethodsPotential studies were searched and selected through the Pubmed/MEDLINE, EMBASE, the China National Knowledge Infrastructure (CNKI) platforms, WanFang and VIP database up to June 2013. Two investigators independently reviewed full text and included studies met inclusion criteria. Combined odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in a fixed-effects model or a random-effects model according to results of heterogeneity test. All analyses were performed by Revman 5.2 and Stata 10.0 software.ResultsA total of 10 studies were included in our meta-analysis, including 3,580 glioma patients and 4,728 controls. Overall, ERCC1 C8092A polymorphism was associated with the risk of glioma (AA vs. CC: OR = 1.29, 95%CI: 1.07-1.55, P = 0.01; recessive model: OR = 1.29; 95% CI: 1.07-1.55, P = 0.01). When stratified by ethnicity, significant association was only observed in the Chinese population (AA vs. CC: OR = 1.37, 95%CI: 1.03-1.81, P = 0.03; recessive model: OR = 1.34; 95% CI: 1.02-1.75, P = 0.04). For ERCC2 Lys751Gln polymorphism, no significant association was found between ERCC2 Lys751Gln polymorphism and the risk of glioma in different genetic models. A significant association of ERCC2 Lys751Gln polymorphism with the risk of glioma was identified in the Caucasian population under recessive model (OR = 0.87; 95% CI: 0.78-0.98, P = 0.02), but not in the Chinese population.ConclusionThis meta-analysis suggested that the AA genotype of ERCC1 C8092A polymorphism might increase the susceptibility of glioma in the Chinese population. And the TT genotype of ERCC2 Lys751Gln polymorphism may decrease the risk of glioma in the Caucasian population. But the small number of studies and moderate methodological quality require cautious interpretation of the study results.

Project description:Cataracts are the major eye disorder and have been associated mainly with mutations in lens-specific genes, but cataracts are also frequently associated with complex syndromes. In a large-scale high-throughput ENU mutagenesis screen we analyzed the offspring of paternally treated C3HeB/FeJ mice for obvious dysmorphologies. We identified a mutant suffering from rough coat and small eyes only in homozygotes; homozygous females turned out to be sterile. The mutation was mapped to chromosome 7 between the markers 116J6.1 and D7Mit294;4 other markers within this interval did not show any recombination among 160 F2-mutants. The critical interval (8.6 Mb) contains 3 candidate genes (Apoe, Six5, Opa3); none of them showed a mutation. Using exome sequencing, we identified a c.2209T>C mutation in the Xpd/Ercc2 gene leading to a Ser737Pro exchange. During embryonic development, the mutant eyes did not show major changes. Postnatal histological analyses demonstrated small cortical vacuoles; later, cortical cataracts developed. Since XPD/ERCC2 is involved in DNA repair, we checked also for the presence of the repair-associated histone ?H2AX in the lens. During the time, when primary lens fiber cell nuclei are degraded, ?H2AX was strongly expressed in the cell nuclei; later, it demarcates clearly the border of the lens cortex to the organelle-free zone. Moreover, we analyzed also whether seemingly healthy heterozygotes might be less efficient in repair of DNA damage induced by ionizing radiation than wild types. Peripheral lymphocytes irradiated by 1Gy Cs137 showed 6 hrs after irradiation significantly more ?H2AX foci in heterozygotes than in wild types. These findings demonstrate the importance of XPD/ERCC2 not only for lens fiber cell differentiation, but also for the sensitivity to ionizing radiation. Based upon these data, we hypothesize that variations in the human XPD/ERCC2 gene might increase the susceptibility for several disorders besides Xeroderma pigmentosum in heterozygotes under particular environmental conditions.

Dataset Information

Association Between ERCC1 rs3212986 and ERCC2/XPD rs1799793 and OS in Patients With Advanced Esophageal Cancer.

Publications

Association Between <i>ERCC1</i> rs3212986 and <i>ERCC2/XPD</i> rs1799793 and OS in Patients With Advanced Esophageal Cancer.

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