Candidate pathway-based genetic association study of platinum and platinum–taxane related toxicity in a cohort of primary lung cancer patients

Abstract

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity secondary to chemotherapy. Genetic factors may be important in predisposing patients to this adverse effect. Patients and Methods We studied 950 primary lung cancer patients, who received platinum or platinum-combination drug chemotherapy and who had DNA available for study. We analyzed epidemiological risk factors in 279 CIPN patients and 456 non-CIPN patients and genetic risk factors in 141 CIPN patients and 259 non-CIPN patients. The risk factors studied included demographic, diagnostic, and treatment data, as well as 174 tag SNPs (single nucleotide polymorphisms) across 43 candidate genes in the glutathione, cell cycle, DNA repair, cell signaling, and apoptosis pathways. Results Patients who had diabetes mellitus were more likely to have CIPN (p=0.0002). Other epidemiologic risk factors associated with CIPN included number of cycles (p=0.0004) and type of concurrent chemotherapy (p<0.001) . SNPs most associated with CIPN were in glutathione peroxidase 7 (GPX7) gene (p values 0.0015 and 0.0028, unadjusted and adjusted) and in ATP-binding cassette sub-family C member 4 (ABCC4) gene (p values 0.037 and 0.006, unadjusted and adjusted). We also found other suggestive associations in methyl-o-guanine-methyl-transferase (MGMT) and glutathione-S-transferase (GST) isoforms. Conclusions Epidemiological and genetic risk factors associated with CIPN in this cohort, included the type of chemotherapy drug, intensity of chemotherapy treatment, and genes known to be associated with chemotherapy resistance. These findings suggest that differentiating between cytotoxic and neurotoxic mechanisms of chemotherapy drugs is challenging but represents an important step toward individualized therapy and improving quality of life for patients.

Incidence and disease burden of chemotherapy-induced peripheral neuropathy in a population-based cohort

“…The current study did not identify statistically significant risk factors for CIPN that have been reported previously, namely diabetes mellitus10 and age 11. This may be because these risk factors have not been clarified with all neurotoxic chemotherapy agents.…”

Neurotoxicity to DRG neurons varies between rodent strains treated with cisplatin and bortezomib

“…Beutler et al, identified heterozygous single nucleotide variants (SNV) in PRX, involved in stabilization of myelin in the peripheral nervous system and ARHGEF10, a gene involved in cytoskeleton and microtubule dynamics. In a separate study Johnson and colleagues found over-representation of polymorphisms in the glutathione peroxidase 7 (GPX7) and ATP-binding cassette sub-family C member 4 (ABCC4) genes in patients developing CIPN when treated with the combination of cisplatin and paclitaxel [26]. …”

Efflux Transporter Variants as Predictors of Drug Toxicity in Lung Cancer Patients: Systematic Review and Meta-Analysis

“…A systematic review is given for efflux transporter genes ABCA1 [37,38], ABCC4 [39], ABCC5 [25], ABCC11 [40] and ABCC12 [40].…”

“…Patient sample size varied widely, ranging between 14 and 731 (total 3578; median 90), with the majority of patient ethnicity being derived from east Asia (Table 1). Many studies focused on patients with advanced stages of NSCLC (stage III and IV), however, cancer type and stages were not given for eight studies (Table 1) [26,27,31,38,39,[41][42][43]. Of the studies described here only five documented the smoking status for their patient cohort [21,34,[44][45][46][47][48].…”

“…rs1729786 Platinumtaxane Peripheral neuropathy [39] Carboplatin/ paclitaxel future science group Efflux transporter variants as predictors of drug toxicity in lung cancer patients Systematic Review rs1045642 and rs2235015, all of which were significantly associated with nausea (p = 0.045) but not neutropenia, thrombocytopenia or diarrhea [28].…”