Dataset Information

UGT1A16, UGT1A73 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.

ABSTRACT: Irinotecan-induced severe neutropenia and diarrhea, which remain unpredictable, has restrained the dose and clinical efficiency of irinotecan administration. In the present study, a total of 70 irinotecan-treated patients with histologically confirmed metastatic gastrointestinal cancer were enrolled. Despite genotyping well-reported alleles, direct sequencing was specifically adopted to avoid ethnic heterogeneity and to identify novel variations. The promoter (-1000 bp) and exon 1 regions of UDP glucuronosyltransferase family 1 member A complex locus (UGT1A1) gene family members UGT1A1, UGT1A7 and UGT1A9 were sequenced, and comprehensive analysis of their genetic polymorphisms was performed to determine the association between inherited genetic variations and irinotecan-induced toxicity. A total of 23 different genetic variants were detected in the present study, including 2 novel polymorphisms. The results of the present study revealed that UGT1A1*6 and UGT1A7*3 are risk factors for irinotecan-induced severe neutropenia, and UGT1A9*1b is associated with severe diarrhea. These results may provide biomarkers for the selection of the optimal chemotherapy for Chinese patients with metastatic gastrointestinal cancer.

SUBMITTER: Cui C

PROVIDER: S-EPMC5104260 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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UGT1A16, UGT1A73 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.

Cui Chengxu C Shu Chang C Cao Dandan D Yang Yi Y Liu Junbao J Shi Shuping S Shao Zhujun Z Wang Nan N Yang Ting T Liang Hao H Zou Shanshan S Hu Songnian S

Oncology letters 20160914 5

Irinotecan-induced severe neutropenia and diarrhea, which remain unpredictable, has restrained the dose and clinical efficiency of irinotecan administration. In the present study, a total of 70 irinotecan-treated patients with histologically confirmed metastatic gastrointestinal cancer were enrolled. Despite genotyping well-reported alleles, direct sequencing was specifically adopted to avoid ethnic heterogeneity and to identify novel variations. The promoter (-1000 bp) and exon 1 regions of UDP ...[more]

PMID: 27895797

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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.

Dataset Information

UGT1A16, UGT1A73 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.

Publications

UGT1A16, UGT1A73 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.

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UGT1A1*6, UGT1A7*3 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.

Publications

UGT1A1*6, UGT1A7*3 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

UGT1A16, UGT1A73 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.

UGT1A16, UGT1A73 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens.