An ERCC4 regulatory variant predicts grade-3 or -4 toxicities in patients with advanced non-small cell lung cancer treated by platinum-based therapy.
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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.
Carcinoma, Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
Polymorphism, Single Nucleotide
Aged, 80 and over
Published Version (Please cite this version)10.1002/ijc.31153
Publication InfoZhang, Ruoxin; Jia, Ming; Xu, Yuan; Qian, Danwen; Wang, Mengyun; Zhu, Meiling; ... Wei, Qingyi (2018). An ERCC4 regulatory variant predicts grade-3 or -4 toxicities in patients with advanced non-small cell lung cancer treated by platinum-based therapy. International journal of cancer, 142(6). pp. 1218-1229. 10.1002/ijc.31153. Retrieved from https://hdl.handle.net/10161/18516.
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Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally recognized epidemiologist focused on the molecular and genetic epidemiology of head and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and genetic determinants for the DNA repair deficient phenotype and