Abstract
Platinum-based chemotherapy is a major therapeutic regimen of lung cancer. Various single nucleotide polymorphisms (SNPs) reported were associated with platinum-based chemotherapy response and drug toxicity. However, neither of the studies explored this association from SNP-SNP interaction perspective nor taking into effects of SNP-environment consideration simultaneously. We genotyped 504 polymorphisms and explore the association of gene-gene and gene-environment interactions with platinum-based chemotherapy response and toxicity in 490 NSCLC patients. 16 SNPs were found significantly associated with platinum-based chemotherapy, and they were picked out as study object in the validation cohort. We recruited 788 patients in the validation cohort. We found that HSPD1 rs17730989-SUMF1 rs2633851 interaction was associated with platinum-based chemotherapy-induced hematologic toxicity (adjusted OR = 0.233, P = 0.018). In addition, the combined effect of ABCG2 rs2231142-CES5A rs3859104 was significantly associated with overall toxicity (adjusted OR = 8.044, P = 4.350 × 10−5). Besides, the model of ARHGAP26 rs3776332-ERCC6 rs2228528-SLC2A1 rs4658-histology was associated with platinum-based chemotherapeutic response. Gene-gene and gene-environment interactions have been identified to contribute to chemotherapy sensitivity and toxicity. They can potentially predict drug response and toxicity of platinum-based chemotherapy in NSCLC patients.
Highlights
Lung cancer is one of the leading causes of cancer related death worldwide[1]
Lung cancer consists of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in histology according to World Health Organization (WHO) classification, and NSCLC accounts for approximately 85% of all cases[4]
We enrolled 504 SNPs in the first stage, a total of 16 interactional SNPs were found remarkably associated with chemotherapy response or toxicities in this cohort (Fig. 1 and supplementary Table S3) We found that the paired interaction between SLC2A1 rs4658 and HSPD1 rs17730989 was significantly associated with platinum-based chemotherapy response in NSCLC patients, indicating the two-locus model of SLC2A1 rs4658-HSPD1 rs17730989 might be related to drug sensitivity
Summary
Lung cancer is one of the leading causes of cancer related death worldwide[1]. In China, lung cancer accounts for 17.09% and 21.68% cases of all cancer incidences and mortalities respectively[2, 3]. Our and others’ previous studies showed that genetic variations were one of the major causes for inter-individual difference of these phenotypes[5,6,7,8,9]. In the case of platinum-based chemotherapy, a number of SNPs have been reported to be associated with drug response as well as ADR10, 11. Since analyzing one single SNP at a time is under powered for complex phenotypes of drug resistance and toxicity, we wanted to explore whether environmental factors combined with genes can achieve better predictive outcomes. Current pharmacogenomics studies of platinum-based chemotherapy in NSCLC only considered the effect of a single SNP and paid no attention to effects of gene-gene and gene-environment interactions. In the present investigation, based on these SNPs, we further explored the effects of gene-gene and gene-environment interactions on platinum-based chemotherapy response and toxicity in Chinese NSCLC patients
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