Genetic Variants in DNA Repair Predicts the Survival of Patients with Esophageal Cancer

Lee, Jang-Ming; Yang, Pei-Wen; Yang, Shi-Yi; Chuang, Tzu-Hsuen; Tung, En-Chi; Chen, Jin‐Shing; Huang, Pei-Ming; Lee, Yung-Chie

doi:10.1097/sla.0b013e318216f374

Cited by 23 publications

(9 citation statements)

References 48 publications

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“…While five of these SNPs were not associated with progression-free survival among HNC cases, four SNPs appeared to be associated with worse progression-free survival contrary to our study [10, 16]. Among esophageal cancer cases, a study by Lee et al [41] did assess rs3136038 reporting better overall survival associated with the genotype TT, though HRs were not statistically significant, similar to our study. Further, ERCC4 protein expression has been found to be elevated in HNC cell lines and displayed cisplatin resistance [42].…”

Section: Discussionsupporting

confidence: 58%

Single nucleotide polymorphisms in nucleotide excision repair genes, cancer treatment, and head and neck cancer survival

Wyss

Weissler

Avery

et al. 2014

Cancer Causes Control

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Purpose Head and neck cancers (HNC) are commonly treated with radiation and platinum-based chemotherapy, which produce bulky DNA adducts to eradicate cancerous cells. Because nucleotide excision repair (NER) enzymes remove adducts, variants in NER genes may be associated with survival among HNC cases both independently and jointly with treatment. Methods Cox proportional hazards models were used to estimate race-stratified (White, African American) hazard ratios (HRs) and 95 % confidence intervals for overall (OS) and disease-specific (DS) survival based on treatment (combinations of surgery, radiation, and chemotherapy) and 84 single nucleotide polymorphisms (SNPs) in 15 NER genes among 1,227 HNC cases from the Carolina Head and Neck Cancer Epidemiology Study. Results None of the NER variants evaluated were associated with survival at a Bonferroni-corrected alpha of 0.0006. However, rs3136038 [OS HR = 0.79 (0.65, 0.97), DS HR = 0.69 (0.51, 0.93)] and rs3136130 [OS HR = 0.78 (0.64, 0.96), DS HR = 0.68 (0.50, 0.92)] of ERCC4 and rs50871 [OS HR = 0.80 (0.64, 1.00), DS HR = 0.67 (0.48, 0.92)] of ERCC2 among Whites, and rs2607755 [OS HR = 0.62 (0.45, 0.86), DS HR = 0.51 (0.30, 0.86)] of XPC among African Americans were suggestively associated with survival at an uncorrected alpha of 0.05. Three SNP-treatment joint effects showed possible departures from additivity among Whites. Conclusions Our study, a large and extensive evaluation of SNPs in NER genes and HNC survival, identified mostly null associations, though a few variants were suggestively associated with survival and potentially interacted additively with treatment.

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Section: Discussionsupporting

confidence: 58%

Single nucleotide polymorphisms in nucleotide excision repair genes, cancer treatment, and head and neck cancer survival

Wyss

Weissler

Avery

et al. 2014

Cancer Causes Control

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“…In the present study, we found that the ERCC2 / XPD rs238406 TT genotype was associated with a reduced DFS and OS in ESCC patients, but few studies have reported its role in prognosis of cancer patients. One Taiwan study found that ERCC2 / XPD rs238406 CC (or GG of its antisense) instead of the AA (or TT of its antisense) genotype of 185 ESCC patients with neoadjuvant chemoirradiation followed by esophagectomy could additively increase risk of death and disease progression in cisplatin-based neoadjuvant concurrent chemoradiation therapy [ 34 ]. Contrary to their results, the TT genotype was associated with the worse DFS and OS in the present study.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants of DNA repair genes predict the survival of patients with esophageal squamous cell cancer receiving platinum-based adjuvant chemotherapy

et al. 2016

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BackgroundAdjuvant chemotherapy in patients with resected esophageal squamous cell cancer (ESCC) remains controversial for its uncertain role in improving overall survival (OS). Nucleotide excision repair (NER) removes DNA-adducts in tumor cells induced by the platinum-based chemotherapy and thus may modulate efficacy of the treatment. The present study evaluated if single nucleotide polymorphisms (SNPs) of NER genes were prognostic biomarkers in ESCC patients treated with platinum-based adjuvant chemotherapy (PAC).MethodsThe analysis included 572 patients, for whom six SNPs of NER genes [i.e., XPC (rs1870134 and rs2228001), ERCC2/XPD rs238406 and ERCC5/XPG (rs2094258, rs2296147 and rs873601)] were detected with the TaqMan assay. Kaplan–Meier analyses and Cox proportional hazards models were used to evaluate their associations with disease free survival (DFS) and OS of these ESCC patients receiving PAC. Receiving operating characteristic curve analysis was used to evaluate the role of the risk genotypes in the DFS and OS.ResultsWe found that ERCC5/XPG rs2094258 and rs873601 and ERCC2/XPD rs238406 SNPs were independently associated with poorer DFS and OS of ESCC patients [ERCC5/XPG rs2094258: CT+TT vs. CC: adjusted hazards ratio (adjHR) = 1.68 and P = 0.012 for DFS; adjHR = 1.99 and P = 0.0001 for OS; ERCC5/XPG rs873601: GA+GG vs. AA: adjHR = 1.59 and P = 0.024 for DFS; adjHR = 1.91 and P = 0.0005 for OS; ERCC2/XPD rs238406: TT vs. GG+GT: adjHR = 1.43 and P = 0.020 for DFS; adjHR = 1.52 and P = 0.008 for OS]. These HRs increased as the number of risk genotypes increased in the combined analysis. The model combining the risk genotypes with clinical characteristics or the TNM stage system was better in predicting outcomes in ESCC patients with PAC.ConclusionSNPs of ERCC2/XPD and ERCC5/XPG may independently and jointly predict survival of ESCC patients treated with PAC in this study population. Further validation in other study populations is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0903-z) contains supplementary material, which is available to authorized users.

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“…Development of better preventive approaches and more effective treatment modalities requires in-depth understanding of molecular mechanisms involved in the complex process of esophageal carcinogenesis. There is an urgent need for identification of novel molecular markers to provide the clinician with useful information concerning patient prognosis and possible therapeutic options [20-22]. In search of molecular markers our laboratory analyzed global gene expression profiles of ESCCs using commercially available 19.1k cDNA microarrays [23].…”

Section: Introductionmentioning

confidence: 99%

Slug Is a Predictor of Poor Prognosis in Esophageal Squamous Cell Carcinoma Patients

et al. 2013

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BackgroundSlug, a regulator of epithelial mesenchymal transition, was identified to be differentially expressed in esophageal squamous cell carcinoma (ESCC) using cDNA microarrays by our laboratory. This study aimed to determine the clinical significance of Slug overexpression in ESCC and determine its correlation with clinicopathological parameters and disease prognosis for ESCC patients. MethodsImmunohistochemical analysis of Slug expression was carried out in archived tissue sections from 91 ESCCs, 61 dysplastic and 47 histologically normal esophageal tissues. Slug immunopositivity in epithelial cells was correlated with clinicopathological parameters and disease prognosis over up to 7.5 years for ESCC patients. ResultsIncreased expression of Slug was observed in esophageal dysplasia [cytoplasmic, 24/61 (39.3%) cases, p = 0.001, odd’s ratio (OR) = 4.7; nuclear, 11/61 (18%) cases, p < 0.001, OR = 1.36] in comparison with normal esophageal tissues. The Slug expression was further increased in ESCCs [cytoplasmic, 64/91 (70.3%) p < 0.001, OR = 10.0; nuclear, 27/91 (29.7%) p < 0.001, OR = 1.42]. Kaplan Meier survival analysis showed significant association of nuclear Slug accumulation with reduced disease free survival of ESCC patients (median disease free survival (DFS) = 6 months, as compared to those that did not show overexpression, DFS = 18 months; p = 0.006). In multivariate Cox regression analysis nuclear Slug expression [p= 0.005, Hazard’s ratio (HR) = 2.269, 95% CI = 1.289 - 3.996] emerged as the most significant independent predictor of poor prognosis for ESCC patients. ConclusionsAlterations in Slug expression occur in early stages of development of ESCC and are sustained during disease progression. Slug may serve as a diagnostic biomarker and as a predictor of poor disease prognosis to identify ESCC patients that are likely to show recurrence of the disease.

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Genetic Variants in DNA Repair Predicts the Survival of Patients with Esophageal Cancer

Abstract: Genetic variants in ERCC2 and ERCC4 may provide further survival prediction in addition to TNM staging system of esophageal cancer, which is more evident in the patients with early disease status.

Cited by 23 publications

References 48 publications

Single nucleotide polymorphisms in nucleotide excision repair genes, cancer treatment, and head and neck cancer survival

Single nucleotide polymorphisms in nucleotide excision repair genes, cancer treatment, and head and neck cancer survival

Genetic variants of DNA repair genes predict the survival of patients with esophageal squamous cell cancer receiving platinum-based adjuvant chemotherapy

Slug Is a Predictor of Poor Prognosis in Esophageal Squamous Cell Carcinoma Patients

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