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

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.

SUBMITTER: Gong WJ

PROVIDER: S-EPMC5386317 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Gong Wei-Jing WJ Peng Jing-Bo JB Yin Ji-Ye JY Li Xiang-Ping XP Zheng Wei W Xiao Ling L Tan Li-Ming LM Xiao Di D Chen Yi-Xin YX Li Xi X Zhou Hong-Hao HH Liu Zhao-Qian ZQ

Acta pharmacologica Sinica 20170306 4

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 lu ...[more]

PMID: 28260796

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Project description:Background and objectiveOverexpression of COX-2 is proved to contribute to tumor promotion and carcinogenesis through stimulating cell proliferation, inhibiting apoptosis and enhancing the invasiveness of cancer cells. Apoptosis-related molecules are potential predictive markers for survival and toxicity in platinum treatment. This study aimed at investigating the association between COX-2 polymorphisms and the occurrence of grade 3 or 4 toxicity in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.Materials and methodsTwo hundred and twelve patients with inoperable stage IIIB-IV NSCLC received first-line chemotherapy between 2007 and 2009 were recruited in this study. Four functional COX-2 polymorphisms were genotyped by PCR-based restriction fragment length polymorphism (RFLP) methods.ResultsThe incidence of grade 3 or 4 hematologic toxicity was significantly higher in G allele carriers of the COX-2 rs689466 (-1195G/A) polymorphism compared with wild-type homozygotes AA (P value = 0.008; odds ratio, 2.47; 95% confidence internal, 1.26-4.84) and the significance still existed after the Bonferroni correction. Statistically significant difference was also found in grade 3 or 4 leukopenia (P value = 0.010; OR = 2.82; 95%CI = 1.28-6.20). No other significant association was observed between genotype and toxicity in the study. The haplotype analysis showed that the haplotype AGG was associated with a reduced risk of grade 3 or 4 hematologic and leukopenia toxicity (P value = 0.009; OR = 0.59; 95%CI = 0.39-0.88 and P value = 0.025; OR = 0.61; 95%CI = 0.39-0.94, respectively) while the haplotype GGG was associated with an increased risk of grade 3 or 4 hematologic and leukopenia toxicity (P value = 0.009; OR = 1.71; 95%CI = 1.14-2.56 and P value = 0.025; OR = 1.65; 95%CI = 1.06-2.57, respectively).ConclusionThis investigation for the first time suggested that polymorphism in COX-2 rs689466 may be a potent bio-marker in predicting severe hematologic toxicity in NSCLC patients after platinum-based chemotherapy.

Project description:BackgroundIrinotecan (CPT11) is an important drug for small cell lung cancer (SCLC) chemotherapy (CTx). UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms can influence CPT11-related toxicity. This study aimed to assess prevalence of UGT1A1 polymorphisms and their association with clinical outcomes in patients with SCLC on CPT11-CTx.MethodsAn observational cohort of treatment-naïve patients with SCLC was given CPT11-platinum doublet at a referral center in North India over 3 years. Clinical outcomes assessed were hematological and gastrointestinal toxicity (Common Terminology Criteria for Adverse Events, version 3.0), response rates (RECIST), and overall survival (OS). Peripheral blood was drawn from all enrolled patients just prior to CPT11-CTx initiation, and genomic DNA was isolated. Genotyping was done by polymerase chain reaction (PCR)-restriction fragment length polymorphism for UGT1A1*7, UGT1A1*6, and UGT1A1*27 and by PCR-DNA sequencing for UGT1A1*28. Patients were classified as homozygous wild-type (WT/WT), heterozygous mutant (WT/M), or homozygous mutant (M/M) for each polymorphism assessed.ResultsOf 140 patients enrolled, no mutant alleles were found for UGT1A1*27 or UGT1A1*7. Frequency of UGT1A1*6 polymorphisms (n = 111) was 89.2% for WT/WT, 8.1% for WT/M, and 2.7% for M/M. For UGT1A1*28 (n = 102), this was 41.2% for WT/WT, 43.1% for WT/M, and 15.7% for M/M. UGT1A1*6 WT/WT patients tolerated >95% predicted CPT11 dose more frequently (59.6% vs. 25.0% in WT/M-M/M combined group; p = .026). The UGT1A1*6 WT/M-M/M group also experienced severe (grade ≥3) diarrhea (41.7% vs. 17.2% in WT/WT; p = .044) and mucositis (41.7% vs. 8.1% in WT/WT; p = .005) more frequently. On multivariate logistic regression analysis, UGT1A1*6 WT/M-M/M status was the only variable associated with occurrence of both mucositis (odds ratio [OR], 10.4) and severe diarrhea (OR, 4.8). UGT1A1*28 WT/M-M/M patients had better OS (320 days [95% confidence interval, 203-437] vs. 216 days [95% confidence interval, 140-292] in WT/WT group; p = .047). On multivariate Cox proportional hazards analysis, UGT1A1*28 WT/M-M/M status was independently associated with better OS (hazard ratio, 0.35), whereas lack of objective radiological response, moderate/heavy smoking, and increasing age were associated with worse OS.ConclusionUGT1A1*6 and UGT1A1*28 polymorphisms were associated with increased gastrointestinal toxicity and improved OS, respectively, in North Indian patients with SCLC receiving CPT11-CTx.Implications for practiceUGT1A1 gene polymorphisms are known to influence irinotecan-related toxicity. In this prospective cohort study of patients with small cell lung cancer receiving first-line irinotecan-platinum chemotherapy, the prevalence of UGT1A1*6 polymorphisms was found to be 10.8% UGT1A1*6 and 58.8% UGT1A1*28 homo/heterozygous mutant, respectively. UGT1A1*6 homo/heterozygous mutant status was associated with severe diarrhea and mucositis. UGT1A1*28 homo/heterozygous mutant status was independently associated with improved overall survival.

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

Publications

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

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