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Use a survival model to correlate single-nucleotide polymorphisms of DNA repair genes with radiation dose-response in patients with non-small cell lung cancer.

ABSTRACT: This study utilizes a survival model and clinical data with various radiation doses from prospective trials to determine radiation dose-response parameters, such as radiosensitivity, and identify single-nucleotide-polymorphism (SNP) biomarkers that can potentially predict the dose response and guide personalized radiotherapy.The study included 92 consecutive stage-III NSCLC patients with doses varying from 60 to 91Gy. Logistic regression analysis of survival varying with SNP genotype and radiation dose was used to screen candidates for dose-response analysis. The dose-response parameter, represented by D50, was derived by fitting survival data into a model that takes into account both tumor control and treatment mortality. A candidate would be considered as a predictor if the 90% confident intervals (90% CIs) of D50 for the 2 groups stratified by the SNP genotype were separated.One SNP-signature (combining ERCC2:rs238406 and ERCC1:rs11615) was found to predict dose-response. D50 values are 63.7 (90% CI: 53.5-66.3) Gy and 76.1 (90% CI: 71.3, 84.6) Gy for the 2 groups stratified by the genotypes. Using this biomarker-based model, a personalized dose prescription may be generated to improve 2-year survival from ?50% to 85% and ?3% to 73% for hypothetical sensitive and resistant patients, respectively.We have developed a survival model that may be used to identify genomic markers, such as ERCC1/2 SNPs, to predict radiation dose-response and potentially guide personalized radiotherapy.

SUBMITTER: Jin JY

PROVIDER: S-EPMC4702521 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Use a survival model to correlate single-nucleotide polymorphisms of DNA repair genes with radiation dose-response in patients with non-small cell lung cancer.

Jin Jian-Yue JY Wang Weili W Ten Haken Randall K RK Chen Jie J Bi Nan N Sadek Ramses R Zhang Hong H Lawrence Theodore S TS Kong Feng-Ming Spring FM

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 20150804 1

<h4>Purpose</h4>This study utilizes a survival model and clinical data with various radiation doses from prospective trials to determine radiation dose-response parameters, such as radiosensitivity, and identify single-nucleotide-polymorphism (SNP) biomarkers that can potentially predict the dose response and guide personalized radiotherapy.<h4>Methods</h4>The study included 92 consecutive stage-III NSCLC patients with doses varying from 60 to 91Gy. Logistic regression analysis of survival varyi ...[more]

PMID: 26253951

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Project description:ObjectivesWe aimed to determine the associations of genetic polymorphisms of excision repair cross-complementation group 1 (ERCC1) rs11615, xeroderma pigmentosum group D (XPD/ERCC2) rs13181, X-ray repair cross complementing group 1 (XRCC1) rs25487, XRCC3 rs1799794, and breast cancer susceptibility gene 1 (BRCA1) rs1799966 from the DNA repair pathway and multiple drug resistance 1 (MDR1/ABCB1) rs1045642 with response to chemotherapy and survival of non-small cell lung cancer (NSCLC) in a Chinese population.Materials and methodsA total of 352 NSCLC patients were enrolled to evaluate the associations of the six SNPs with response to chemotherapy and overall survival. Logistic regressions were applied to test the associations of genetic polymorphisms with response to chemotherapy in 161 advanced NSCLC patients. Overall survival was analyzed in 161 advanced and 156 early stage NSCLC patients using the Kaplan-Meier method with log-rank test, respectively. Multivariate Cox proportional hazards model was performed to determine the factors independently associated with NSCLC prognosis.ResultsBRCA1 rs1799966 minor allele C (TC+CC vs. TT, OR = 0.402, 95% CI = 0.204-0.794, p = 0.008) and MDR1/ABCB1 rs1045642 minor allele A (GA +AA vs. GG, OR = 0.478, 95% CI = 0.244-0.934, p = 0.030) were associated with a better response to chemotherapy in advanced NSCLC patients. Survival analyses indicated that BRCA1 rs1799966 TC+CC genotypes were associated with a decreased risk of death (HR = 0.617, 95% CI = 0.402-0.948, p = 0.028) in advanced NSCLC patients, and the association was still significant after the adjustment for covariates. Multivariate Cox regression analysis showed that ERCC1 rs11615 AA genotype (P = 0.020) and smoking (p = 0.037) were associated with increased risks of death in early stage NSCLC patients after surgery.ConclusionsPolymorphisms of genes in DNA repair pathway and MDR1 could contribute to chemotherapy response and survival of patients with NSCLC.

Dataset Information

Use a survival model to correlate single-nucleotide polymorphisms of DNA repair genes with radiation dose-response in patients with non-small cell lung cancer.

Publications

Use a survival model to correlate single-nucleotide polymorphisms of DNA repair genes with radiation dose-response in patients with non-small cell lung cancer.

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