ERCC4 regulatory variant predict Grade-3 or -4 toxicities in patients with advanced non-small cell lung cancer treated by platinum-based therapy

Abstract

Platinum-based chemotherapy (PBC) in combination with the 3^rd 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, contributing 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 eight NER core genes with overall, gastrointestinal and hematologic toxicities. Through a two-phase screening 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, P_adj=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 with 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 eQTL analysis. This study provided some new clue in future development of biomarkers for assessing toxicity and outcomes of platinum drugs in cancer treatment. This article is protected by copyright. All rights reserved.

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