Pol ζ polymorphisms are associated with platinum based chemotherapy response and side effects among non-small cell lung cancer patients

Abstract

Lung cancer is the greatest contributor to tumor-derived death. Traditionally, platinum-based chemotherapies are the primary treatment for most patients. However, intrinsic drug resistance and side effects limit the efficacy of platinum-based chemotherapies. Previous studies demonstrated that Pol ζ can modulate cellular sensitivity to chemotherapy. The primary aim of this study was to investigate the potential role of the polymorphism of Pol ζ in platinum-based chemotherapy tolerance and side effects. A total of 663 patients who were newly histologically diagnosed with advanced NSCLC were enrolled. Their treatment response was classified into four categories: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). The gastrointestinal and hematological toxicity incidence was assessed twice a week during the entire first line of treatment. Thirteen SNPs of REV3 and REV7 were genotyped. The associations between SNPs and the treatment response or toxicity were analyzed with a logistic regression model. We discovered that five SNPs were correlated with the treatment response. Specifically, rs240969 was significantly associated with the treatment response, after a Bonferroni correction, in smokers and a combined cohort (P=0.048 and P=0.0082, respectively) as well as with rs3218573 in smokers (P=0.036). In addition, we discovered that the incidence of grade 3 or 4 gastrointestinal toxicity was significantly higher in patients carrying a G/G genotype of rs240966 or an A allele of rs456865. We also identified that five SNPs, namely rs240966, rs4945880, rs465646, rs2233025 and rs2336030, that were correlated with an increased risk of grade 3 or grade 4 hematologic toxicity. The REV3 and REV7 polymorphisms are in a catalytic subunit and an accessory subunit of Pol ζ, respectively, and participate in platinum-chemotherapy tolerance and side effects. Key words: REV3, REV7, Pol ζ, platinum-based chemotherapies, translesion synthesis, toxicityLung cancer is the highest contributor to cancer-related deaths, and non-small cell lung cancer (NSCLC) accounts for nearly 80% of all lung cancer deaths [1]. The incidence rate of lung cancer is rapidly rising due to tobacco use, air pollution, and other cancer-causing factors [2]. Although targeted therapy is very efficient and tremendously improves the progress-free survival (PFS) and overall survival (OS) of lung cancer patients [3][4][5], however,over 70% of patients lack the positive biomarkers that are considered necessary for platinum-based chemotherapies as the traditional front-line treatment [6,7]. The efficacy of platinum-based chemotherapies is severely limited by intrinsic drug resistance. In addition, while platinum can kill uncontrollably dividing tumor cells by coupling to DNA and terminating the replication of DNA, normal cells will also be inevitably damaged [8].Previous studies have shown that DNA repair systems play an essential role in platinum-based chemotherapy tolerance [8][9][10][11]. DNA inter-or intra-crosslinking cause...

The association of genetic variations in DNA repair pathways with severe toxicities in NSCLC patients undergoing platinum‐based chemotherapy

“…Ye et al . divided patients according to smoking status, genotyped 13 tagSNPs of REV3 and REV7 and found that the five SNPs were correlated with an increased risk of grade 3 or 4 hematologic toxicity …”

Safety and Efficacy of Mild Moxibustion on Cancer-Related Fatigue in Non-Small-Cell Lung Cancer Patients Undergoing Chemotherapy

“…(1) patients diagnosed with NSCLC referred to the diagnostic criteria above; (2) 18-80 years old; (3) patients who were about to undergo the first GP chemotherapy, with an 8-day course of treatment (day 1-3 days and 8); (4) no history of surgery within 6 months before chemotherapy; (5) patients who never participated in any fatigue-related interventions; (6) no infection, injury, and ulcer around the acupoints; (7) patients were diagnosed CRF in line with the CRF diagnostic criteria of the 10th edition of the International Statistical Classification of Diseases and Related Health Problems and were rated as mild and moderate fatigue according to the Chinese version of the Piper Fatigue Scale-Revised (RPFS-CV); (8) had a Karnofsky ðKPSÞ efficacy status score > 60 points, with a predicted survival time > 6 months; (9) no cognitive impairment; and (10) voluntarily participated in this study and provided signed informed consent.…”

“…Patients with stages IIb to III lung adenosquamous carcinoma (ASC) are often given platinumbased dual-drug chemotherapy [3] to terminate cancer cell division and inhibit cancer DNA synthesis [4][5][6]. However, these treatments simultaneously damage normal DNA, thereby increasing the risk of gastrointestinal and hematological toxicity [7] and eventually causing fatigue.…”

Genetic variants ofGADD45A, GADD45BandMAPK14predict platinum-based chemotherapy-induced toxicities in Chinese patients with non-small cell lung cancer

“…Platinum compounds induce DNA damage, inhibit DNA replication, and activate a number of signal transduction pathways leading to cancer cell death [ 3 ]. However, these drugs also damage normal cells, leading to severe adverse events [ 4 , 5 ]. Despite initial tumor control, some cancer patients treated with chemotherapies often need to decrease drug doses or stop treatment due to severe adverse events.…”