title: DNA Methylation of PITX2 and PANCR Is Prognostic for Overall Survival in Patients with Resected Adenocarcinomas of the Biliary Tract.
abstract: 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.
authors: Institute of Pathology, University of Bonn, Bonn, Germany.
authors: Barbara
authors: B
authors: Uhl
authors: Institute of Pathology, University of Bonn, Bonn, Germany.|Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Germany.
authors: Dimo
authors: D
authors: Dietrich
authors: Department of Surgery, University of Bonn, Bonn, Germany.
authors: Vittorio
authors: V
authors: Branchi
authors: Department of Surgery, University of Bonn, Bonn, Germany.
authors: Alexander
authors: A
authors: Semaan
authors: Department of Surgery, University of Bonn, Bonn, Germany.
authors: Pauline
authors: P
authors: Schaefer
authors: Institute of Pathology, University of Bonn, Bonn, Germany.
authors: Heidrun
authors: H
authors: Gevensleben
authors: Department of Neuroradiology, Katharinenhospital, Klinikum Stuttgart, Stuttgart, Germany.
authors: Babak
authors: B
authors: Rostamzadeh
authors: Department of Surgery, University of Bonn, Bonn, Germany.
authors: Philipp
authors: P
authors: Lingohr
authors: Department of Surgery, University of Bonn, Bonn, Germany.
authors: Nico
authors: N
authors: Schäfer
authors: Department of Surgery, University of Bonn, Bonn, Germany.
authors: Jörg C
authors: JC
authors: Kalff
authors: Institute of Pathology, University of Bonn, Bonn, Germany.
authors: Glen
authors: G
authors: Kristiansen
authors: Department of Surgery, University of Bonn, Bonn, Germany.
authors: Hanno
authors: H
authors: Matthaei
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001661:Biliary Tract Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D014408:Biomarkers, Tumor; D002894:Chromosomes, Human, Pair 4; D019175:DNA Methylation; D005260:Female; D056426:Genetic Loci; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D022661:RNA, Untranslated / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D022661:RNA, Untranslated; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2