title: A Novel Epigenetic Signature for Early Diagnosis in Lung Cancer.
abstract: Lung cancer remains as the leading cause of cancer-related death worldwide, mainly due to late diagnosis. Cytology is the gold-standard method for lung cancer diagnosis in minimally invasive respiratory samples, despite its low sensitivity. We aimed to identify epigenetic biomarkers with clinical utility for cancer diagnosis in minimally/noninvasive specimens to improve accuracy of current technologies.
  
  
  
  The identification of novel epigenetic biomarkers in stage I lung tumors was accomplished using an integrative genome-wide restrictive analysis of two different large public databases. DNA methylation levels for the selected biomarkers were validated by pyrosequencing in paraffin-embedded tissues and minimally invasive and noninvasive respiratory samples in independent cohorts.
  
  
  
  We identified nine cancer-specific hypermethylated genes in early-stage lung primary tumors. Four of these genes presented consistent CpG island hypermethylation compared with nonmalignant lung and were associated with transcriptional silencing. A diagnostic signature was built using multivariate logistic regression model based on the combination of four genes: BCAT1, CDO1, TRIM58, and ZNF177 Clinical diagnostic value was also validated in multiple independent cohorts and yielded a remarkable diagnostic accuracy in all cohorts tested. Calibrated and cross-validated epigenetic model predicts with high accuracy the probability to detect cancer in minimally and noninvasive samples. We demonstrated that this epigenetic signature achieved higher diagnostic efficacy in bronchial fluids as compared with conventional cytology for lung cancer diagnosis.
  
  
  
  Minimally invasive epigenetic biomarkers have emerged as promising tools for cancer diagnosis. The herein obtained epigenetic model in combination with current diagnostic protocols may improve early diagnosis and outcome of lung cancer patients. Clin Cancer Res; 22(13); 3361-71. ©2016 AACR.
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
authors: Angel
authors: A
authors: Diaz-Lagares
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
authors: Jesus
authors: J
authors: Mendez-Gonzalez
authors: Biostatistics Unit, Medical Research Institute La Fe, Valencia, Spain.
authors: David
authors: D
authors: Hervas
authors: Department of Medical Oncology, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain.
authors: Maria
authors: M
authors: Saigi
authors: IDISNA and Program in Solid Tumors and Biomarkers, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.
authors: Maria J
authors: MJ
authors: Pajares
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
authors: Diana
authors: D
authors: Garcia
authors: Laboratory of Molecular and Cellular Endocrinology, Health Research Institute of Santiago (IDIS), University Hospital of Santiago (XXIS/SERGAS), Santiago de Compostela University (USC), Travesia da Choupana S/N, Santiago de Compostela and CIBER of Physiopathology of Obesity and Nutrition (CIBERobn), Madrid, Spain.
authors: Ana B
authors: AB
authors: Crujerias
authors: IDISNA and Program in Solid Tumors and Biomarkers, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Department of Biochemistry and Genetics, School of Science, University of Navarra, Pamplona, Spain.
authors: Ruben
authors: R
authors: Pio
authors: IDISNA and Program in Solid Tumors and Biomarkers, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.
authors: Luis M
authors: LM
authors: Montuenga
authors: Pulmonary Department, Clínica Universidad de Navarra, Pamplona, Spain.
authors: Javier
authors: J
authors: Zulueta
authors: Department of Medical Oncology, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain.
authors: Ernest
authors: E
authors: Nadal
authors: Pneumology Department, Hospital University Bellvitge, IDIBELL, L'Hospitalet, Barcelona and CIBER of Respiratory diseases (CIBERes), Madrid, Spain.
authors: Antoni
authors: A
authors: Rosell
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain. Catalan Institution for Research and Advanced Studies (ICREA) and Passeig de Lluís Companys, Barcelona, Catalonia, Spain. juan.sandoval@uv.es mesteller@idibell.cat.
authors: Manel
authors: M
authors: Esteller
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain. juan.sandoval@uv.es mesteller@idibell.cat.
authors: Juan
authors: J
authors: Sandoval
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D050558:Cysteine Dioxygenase / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D055088:Early Detection of Cancer / Q000379:methods; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D000637:Transaminases / Q000235:genetics*; D000070584:Tripartite Motif Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D000070584:Tripartite Motif Proteins; C100934:ZNF177 protein, human; C579734:CDO1 protein, human; D050558:Cysteine Dioxygenase; C490590:BCAT1 protein, human; D000637:Transaminases