RAD18 polymorphisms are associated with platinum-based chemotherapy toxicity in Chinese patients with non-small cell lung cancer

Abstract

Aim: Although targeted therapy is very efficient for lung cancer, traditional platinum-based chemotherapies are still the principal strategy in the absence of positive biomarkers. The aim of the present study is to evaluate the contribution of RAD18 polymorphisms to platinum-chemotherapy response and its potential side effects in Chinese patients with non-small cell lung cancer (NSCLC). Methods: A total of 1021 Chinese patients with histological diagnosis of advanced NSCLC were enrolled. Treatment responses were classified into 4 categories (complete response, partial response, stable disease and progressive disease). Gastrointestinal and hematological toxicity incidences were assessed twice a week during the first-line treatment. Ten RAD18 SNPs were genotyped. A logistic regression model was utilized to analyze the associations between RAD18 SNPs and treatment response or toxicity. Results: Among the 10 SNPs tested, none was significantly correlated with the treatment response in a combined cohort. For gastrointestinal toxicity incidences, rs586014 was significantly associated with an increased risk of grade 3 or 4 gastrointestinal toxicity in non-smokers and in the combined cohort; rs654448 and rs618784 were significantly associated with gastrointestinal toxicity in non-smokers; rs6763823 was significantly associated with gastrointestinal toxicity in smokers. For hematological toxicity incidences, rs586014, rs654448 and rs618784 were significantly associated with hematologic toxicity in non-smokers; rs6763823 and rs9880051 were significantly associated with leukocytopenia in smokers. Conclusion: RAD18 polymorphisms are correlated with the side effects of platinum-chemotherapy in Chinese patients with advanced NSCLC.

RAD18 may function as a predictor of response to preoperative concurrent chemoradiotherapy in patients with locally advanced rectal cancer through caspase‐9‐caspase‐3‐dependent apoptotic pathway

“…Many previous studies have revealed that abnormal expression of RAD18 could be found in different cancer cells . High RAD18 expression enhances translesion synthesis and double‐strand breaks repair, leading to tolerance of DNA damage and replication stress, thus resulting in chemo‐resistance . High RAD18 level in cancer cells also represents extreme resistance to IR by regulating DNA damage‐dependent checkpoint and G2/M checkpoint .…”

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

“…Published studies on NER pathway variants and PBC toxicity in NSCLC patients have mainly focused on missense variants, with very few investigating a group of core genes in the pathway or considering LD between the variants or non‐coding variants . In the present study, we employed a hypothesis‐based approach with a main focus on independent regulatory variants with predicted biological functions.…”

“…26,27 Published studies on NER pathway variants and PBC toxicity in NSCLC patients have mainly focused on missense variants, with very few investigating a group of core genes in the pathway or considering LD between the variants or noncoding variants. 24,28,29 In the present study, we employed a hypothesis-based approach with a main focus on independent regulatory variants with predicted biological functions. Based on a two-phase screening design, we observed that under a dominant genetic model the ERCC4 rs1799798 SNP had a significant effect on both overall and GI toxicity outcomes in advanced Chinese NSCLC patients treated with PBC, it is possible that the rs1799798 A allele associated with a higher risk of overall toxicity was driven by its association with GI toxicity ( Table 2).…”

Toxicity and pharmacokinetic biomarkers for personalized non-small cell lung cancer treatment

“…Associations with neutropenia have been identified but the results have been contradictory [96][97][98][99][100]. Moreover, SNPs associated with hematological toxicity in DNA repair pathways have been extensively studied in several platinum-based chemotherapy combinations [100][101][102][103][104][105]. These genes are mainly located in the nucleotide excision repair pathway responsible for repairing intra-strand crosslinks.…”

“…These genes are mainly located in the nucleotide excision repair pathway responsible for repairing intra-strand crosslinks. SNPs in ERCC2, IL16, MMS19L, RAD18, XPC, XPD, and XRCC1 have for instance been associated with either hematological toxicity or leukopenia [101,103,[105][106][107][108].…”