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An ERCC4 regulatory variant predicts grade-3 or -4 toxicities in patients with advanced non-small cell lung cancer treated by platinum-based therapy.

dc.contributor.author Wei, Qingyi
dc.contributor.author Zhang, Ruoxin
dc.contributor.author Jia, Ming
dc.contributor.author Xu, Yuan
dc.contributor.author Qian, Danwen
dc.contributor.author Wang, Mengyun
dc.contributor.author Zhu, Meiling
dc.contributor.author Sun, Menghong
dc.contributor.author Chang, Jianhua
dc.date.accessioned 2019-05-01T18:35:34Z
dc.date.available 2019-05-01T18:35:34Z
dc.date.issued 2018-03
dc.identifier.issn 0020-7136
dc.identifier.issn 1097-0215
dc.identifier.uri https://hdl.handle.net/10161/18516
dc.description.abstract Platinum-based chemotherapy (PBC) in combination with the 3rd generation drugs is the first-line treatment for patients with advanced non-small cell lung cancer (NSCLC); however, the efficacy is severely hampered by grade 3-4 toxicities. Nucleotide excision repair (NER) pathway is the main mechanism of removing platinum-induced DNA adducts that contribute to the toxicity and outcome of PBC. We analyzed data from 710 Chinese NSCLC patients treated with PBC and assessed the associations of 25 potentially functional single nucleotide polymorphisms (SNPs) in nine NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two-phase study, we found that ERCC4 rs1799798 was significantly associated with overall and gastrointestinal toxicities [all patients: GA/AA vs. GG, odds ratio (OR)adj =1.61 and 2.35, 95% confidence interval (CI)=1.11-2.33 and 1.25-4.41, and Padj =0.012 and 0.008, respectively]. Our prediction model for the overall toxicity incorporating rs1799798 demonstrated a significant increase in the area under the curve (AUC) value, compared to that for clinical factors only (all patients: AUC = 0.61 vs. 0.59, 95% CI = 0.57-0.65 vs. 0.55-0.63, P = 0.010). Furthermore, the ERCC4 rs1799798 A allele was associated with lower ERCC4 mRNA expression levels according to the expression quantitative trait loci (eQTL) analysis. Our study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in lung cancer treatment.
dc.language eng
dc.publisher Wiley
dc.relation.ispartof International journal of cancer
dc.relation.isversionof 10.1002/ijc.31153
dc.subject Humans
dc.subject Carcinoma, Non-Small-Cell Lung
dc.subject Lung Neoplasms
dc.subject Gastrointestinal Diseases
dc.subject Hematologic Diseases
dc.subject Organoplatinum Compounds
dc.subject DNA-Binding Proteins
dc.subject DNA Adducts
dc.subject RNA, Messenger
dc.subject Antineoplastic Combined Chemotherapy Protocols
dc.subject Computational Biology
dc.subject DNA Repair
dc.subject Polymorphism, Single Nucleotide
dc.subject Adult
dc.subject Aged
dc.subject Aged, 80 and over
dc.subject Middle Aged
dc.subject Female
dc.subject Male
dc.subject Young Adult
dc.subject Biomarkers, Tumor
dc.title An ERCC4 regulatory variant predicts grade-3 or -4 toxicities in patients with advanced non-small cell lung cancer treated by platinum-based therapy.
dc.type Journal article
dc.date.updated 2019-05-01T18:35:33Z
pubs.begin-page 1218
pubs.end-page 1229
pubs.issue 6
pubs.organisational-group School of Medicine
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group Population Health Sciences
pubs.organisational-group Basic Science Departments
pubs.organisational-group Medicine, Medical Oncology
pubs.organisational-group Medicine
pubs.organisational-group Clinical Science Departments
pubs.publication-status Published
pubs.volume 142
duke.contributor.orcid Wei, Qingyi|0000-0002-3845-9445


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