Association between well-characterized lung cancer IncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer  

作　　者：Wei-jing GONG Jing-bo PENG Ji-ye YIN Xiang-ping LI Wei ZHENG Ling XIAO Li-ming TAN Di XIAO Yi-xin CHEN Xi LI Hong-hao ZHOU Zhao-qian LIU 

机构地区：[1]Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China [2]Institute of Clinical Pharmacology, Central South University, Hu-nan Key Laboratory of Pharmacogenetics, Changsha 410078, China [3]Hu-nan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, China [4]Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China

出　　处：《Acta Pharmacologica Sinica》2017年第4期581-590,共10页中国药理学报（英文版）

基　　金：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）.

摘　　要：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.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.

关 键 词：lung cancer platinum-based chemotherapy gastrointestinal toxicity hematological toxicity long non-coding RNA （IncRNA） POLYMORPHISM Chinese patients 

分 类 号：Q346.5[生物学—遗传学] S948[农业科学—水产养殖]