title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiation Oncology, Georgia Regents University, Augusta, United States.
authors.forename: Jian-Yue
authors.initials: JY
authors.lastname: Jin
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Weili
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Randall K
authors.initials: RK
authors.lastname: Ten Haken
authors.affiliation: Department of Biostatistics and Epidemiology, Georgia Regents University, Augusta, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Nan
authors.initials: N
authors.lastname: Bi
authors.affiliation: Department of Biostatistics and Epidemiology, Georgia Regents University, Augusta, United States.
authors.forename: Ramses
authors.initials: R
authors.lastname: Sadek
authors.affiliation: Department of Radiation Oncology, Georgia Regents University, Augusta, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, United States.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.affiliation: Department of Radiation Oncology, Georgia Regents University, Augusta, United States. Electronic address: Fkong@gru.edu.
authors.forename: Feng-Ming Spring
authors.initials: FM
authors.lastname: Kong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004307:Dose-Response Relationship, Radiation; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011879:Radiotherapy Dosage; D016019:Survival Analysis; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C071447:ERCC1 protein, human; D004720:Endonucleases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human
keywords: Biomarker; Dose survival model; ERCC1 and ERCC2; Personalized radiotherapy; Radiosensitivity; Single-nucleotide-polymorphisms (SNPs)