DNA Methylation of PITX2 and PANCR Is Prognostic for Overall Survival in Patients with Resected Adenocarcinomas of the Biliary Tract

• Published in: PloS one Vol. 11; no. 10; p. e0165769
• Main Authors: Uhl, Barbara, Dietrich, Dimo, Branchi, Vittorio, Semaan, Alexander, Schaefer, Pauline, Gevensleben, Heidrun, Rostamzadeh, Babak, Lingohr, Philipp, Schäfer, Nico, Kalff, Jörg C, Kristiansen, Glen, Matthaei, Hanno
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31-10-2016; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adenocarcinoma - surgery; Adult; Aged; Aged, 80 and over; Analysis; Biliary tract; Biliary tract cancer; Biliary Tract Neoplasms - genetics; Biliary Tract Neoplasms - mortality; Biliary Tract Neoplasms - pathology; Biliary Tract Neoplasms - surgery; Biology and life sciences; Biomarkers; Biomarkers, Tumor; Breast cancer; Cancer genetics; Care and treatment; Chromosomes, Human, Pair 4; Deoxyribonucleic acid; Development and progression; DNA; DNA Methylation; Epigenetics; Female; Gallbladder; Gene expression; Genetic Loci; Genomes; Homeobox Protein PITX2; Homeodomain Proteins - genetics; Hospitals; Humans; Kaplan-Meier Estimate; Male; Medical diagnosis; Medical prognosis; Medicine and Health Sciences; Methylation; Middle Aged; Multivariate analysis; Neoplasm Grading; Neoplasm Staging; Non-coding RNA; Paraffin; Pathology; Patient outcomes; Patients; Prognosis; Promoter Regions, Genetic; Prostate cancer; Ribonucleic acid; RNA; RNA, Untranslated - genetics; Subpopulations; Surgery; Survival; Transcription Factors - genetics; Tumors; United States > US; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0165769

Biliary tract cancers (BTC) are rare but highly aggressive malignant epithelial tumors. In order to improve the outcome in this lethal disease, novel biomarkers for diagnosis, prognosis, and therapy response prediction are urgently needed. DNA promoter methylation of PITX2 variants (PITX2ab, PITX2c) and intragenic methylation of the PITX2 adjacent non-coding RNA (PANCR) were investigated by methylations-specific qPCR assays in formalin-fixed paraffin-embedded tissue from 80 patients after resection for BTC. Results were correlated with clinicopathologic data and outcome. PITX2 variants and PANCR showed significant hypermethylation in tumor vs. normal adjacent tissue (p < 0.001 and p = 0.015), respectively. In survival analysis, dichotomized DNA methylation of variant PITX2c and PANCR were significantly associated with overall survival (OS). Patients with high tumor methylation levels of PITX2c had a shorter OS compared to patients with low methylation (12 vs. 40 months OS; HR 2.48 [1.38-4.48], p = 0.002). In contrast, PANCR hypermethylation was associated with prolonged survival (25 vs. 19 months OS; HR 0.54 [0.30-0.94], p = 0.015) and qualified as an independent prognostic factor on multivariate analysis. The biomarkers investigated in this study may help to identify BTC subpopulations at risk for worse survival. Further studies are needed to evaluate if PITX2 might be a clinically useful biomarker for an optimized and individualized treatment.