Abstract
Platinum-based chemotherapy is the standard first-line treatment for most lung cancer patients. However, the toxicity induced by platinum-based chemotherapy greatly impedes its clinical use. Previous studies showed that long non-coding RNAs (lncRNAs) with over 200 nucleotides in length affect drug response and toxicity. In the present study, we investigated the association of well-characterized lung cancer lncRNA polymorphisms with platinum-based chemotherapy toxicity in Chinese patients with lung cancer. A total of 467 lung cancer patients treated with platinum-based chemotherapy for at least two cycles were recruited. We primarily focused on gastrointestinal and hematological toxicities. A total of 14 potentially functional polymorphisms within 8 lncRNAs (HOTTIP, HOTAIT, H19, ANRIL, CCAT2, MALAT1, MEG3, and POLR2E) were genotyped. Unconditional logistical regression analysis was conducted to assess the associations. Gene-gene and gene-environment interactions were identified using the software generalized multifactor dimensionality reduction (GMDR). ANRIL rs1333049 was associated with severe overall toxicity in an additive model (adjusted OR=0.723, 95% CI=0.541–0.965, P=0.028). ANRIL rs1333049 was also associated with severe gastrointestinal toxicity in both the additive (adjusted OR=0.690, 95% CI=0.489–0.974, P=0.035) and dominant (adjusted OR=0.558, 95% CI=0.335–0.931, P=0.025) models. MEG3 rs116907618 was associated with severe gastrointestinal toxicity in an additive model (adjusted OR=1.717, 95% CI=1.007–2.927, P=0.047). GMDR identified the three-factor interaction model of POLR2E rs3787016-HOTTIP rs3807598-chemotherapy regimen as the best predictive model for hematological toxicity. In conclusion, ANRIL and MEG3 genetic polymorphisms are associated with severe platinum toxicity and could be considered as biomarkers for pretreatment evaluation in Chinese patients with lung cancer.
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Acknowledgements
The authors would like to thank all of the patients who participated in the study. This work was supported by the National Key Research and Development Plan (SQ2016YFSF110100 and 2016YFC0905000), National Natural Science Foundation of China (81373490, 81573508, and 81573463), Hunan Provincial Science and Technology Plan of China (2015JC3025), and Open Foundation of Innovative Platform in University of Hunan Province of China (421530004).
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Supplementary information is available at the website of Acta Pharmacologica Sinica.
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Supplementary Table S1
Clinical characteristics of patients with Gastrointestinal toxicity (DOC 59 kb)
Supplementary Table S2
Clinical characteristics of patients with hematologic toxicity. (DOC 61 kb)
Supplementary Table S3
Basic information of SNPs in lncRNAs. (DOC 37 kb)
Supplementary Table S4
The association of gene-gene interaction and toxicity induced by platinum-based chemotherapy. (DOC 25 kb)
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Gong, Wj., Peng, Jb., Yin, Jy. et al. Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer. Acta Pharmacol Sin 38, 581–590 (2017). https://doi.org/10.1038/aps.2016.164
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DOI: https://doi.org/10.1038/aps.2016.164
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