A Novel Epigenetic Signature for Early Diagnosis in Lung Cancer
Diaz-Lagares A (1), Mendez-Gonzalez J ()1, Hervas D (2), Saigi M (3), Pajares MJ (4), Garcia D (1), Crujerias AB (5), Pio R (6), Montuenga LM (4), Zulueta J (7), Nadal E (3), Rosell A (8), Esteller M (9), Sandoval J (10).
(1) Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
(2) Biostatistics Unit, Medical Research Institute La Fe, Valencia, Spain.
(3) Department of Medical Oncology, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain.
(4) 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.
(5) 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.
(6) 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.
(7) Pulmonary Department, Clínica Universidad de Navarra, Pamplona, Spain.
(8) Pneumology Department, Hospital University Bellvitge, IDIBELL, L'Hospitalet, Barcelona and CIBER of Respiratory diseases (CIBERes), Madrid, Spain.
(9) 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.
(10) Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Catalonia, Spain.
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.
CITATION Clin Cancer Res. 2016 Jul 1;22(13):3361-71. doi: 10.1158/1078-0432.CCR-15-2346. Epub 2016 Feb 3