Gong Wei-Jing, Peng Jing-Bo, Yin Ji-Ye, Li Xiang-Ping, Zheng Wei, Xiao Ling, Tan Li-Ming, Xiao Di, Chen Yi-Xin, Li Xi, Zhou Hong-Hao, Liu Zhao-Qian
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, China; Institute of Clinical Pharmacology, Central South University, Hu-nan Key Laboratory of Pharmacogenetics, Changsha 410078, China.
Hu-nan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang 421001, China.
Acta Pharmacol Sin. 2017 Apr;38(4):581-590. doi: 10.1038/aps.2016.164. Epub 2017 Mar 6.
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.
铂类化疗是大多数肺癌患者的标准一线治疗方法。然而，铂类化疗引起的毒性极大地阻碍了其临床应用。先前的研究表明，长度超过200个核苷酸的长链非编码RNA（lncRNA）会影响药物反应和毒性。在本研究中，我们调查了中国肺癌患者中特征明确的肺癌lncRNA多态性与铂类化疗毒性之间的关联。共招募了467例接受铂类化疗至少两个周期的肺癌患者。我们主要关注胃肠道和血液学毒性。对8个lncRNA（HOTTIP、HOTAIT、H19、ANRIL、CCAT2、MALAT1、MEG3和POLR2E）中的14个潜在功能性多态性进行了基因分型。进行无条件逻辑回归分析以评估相关性。使用广义多因素降维（GMDR）软件识别基因-基因和基因-环境相互作用。ANRIL rs1333049在加性模型中与严重的总体毒性相关（调整后的OR=0.723，95%CI=0.541-0.965，P=0.028）。ANRIL rs1333049在加性模型（调整后的OR=0.690，95%CI=0.489-0.974，P=0.035）和显性模型（调整后的OR=0.558，95%CI=0.335-0.931，P=0.025）中也与严重的胃肠道毒性相关。MEG3 rs116907618在加性模型中与严重的胃肠道毒性相关（调整后的OR=1.717，95%CI=1.007-2.927，P=0.047）。GMDR确定POLR2E rs3787016-HOTTIP rs3807598-化疗方案的三因素相互作用模型是血液学毒性的最佳预测模型。总之，ANRIL和MEG3基因多态性与严重的铂毒性相关，可被视为中国肺癌患者预处理评估的生物标志物。
