title: Early Molecular Stratification of High-risk Primary Biliary Cholangitis.
abstract: High-risk primary biliary cholangitis (PBC), defined by inadequate response at one year to Ursodeoxycholic acid (UDCA), is associated with disease progression and liver transplantation. Stratifying high-risk patients early would facilitate improved approaches to care. Using long-term follow-up data to define risk at presentation, 6 high-risk PBC patients and 8 low-risk patients were identified from biopsy, transplant and biochemical archival records. Formalin-fixed paraffin-embedded (FFPE) liver biopsies taken at presentation were graded (Scheuer and Nakanuma scoring) and gene expression analysed using the NanoString® nCounter PanCancer Immunity 770-gene panel. Principle component analysis (PCA) demonstrated discrete gene expression clustering between controls and high- and low-risk PBC. High-risk PBC was characterised by up-regulation of genes linked to T-cell activation and apoptosis, INF-γ signalling and leukocyte migration and down-regulation of those linked to the complement pathway. CDKN1a, up-regulated in high-risk PBC, correlated with significantly increased expression of its gene product, the senescence marker p21WAF1/Cip, by biliary epithelial cells. Our findings suggest high- and low-risk PBC are biologically different from disease outset and senescence an early feature in high-risk disease. Identification of a high-risk 'signal' early from standard FFPE tissue sections has clear clinical utility allowing for patient stratification and second-line therapeutic intervention.
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Hardie
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Kile
authors.initials: K
authors.lastname: Green
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Jopson
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Millar
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Innes
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pagan
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Dina
authors.initials: D
authors.lastname: Tiniakos
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dyson
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Muzlifah
authors.initials: M
authors.lastname: Haniffa
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: David E
authors.initials: DE
authors.lastname: Jones
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: John
authors.initials: J
authors.lastname: Brain
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne, UK. Electronic address: Lucy.walker2@ncl.ac.uk.
authors.forename: Lucy J
authors.initials: LJ
authors.lastname: Walker
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers; D001706:Biopsy; D002761:Cholangitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger
keywords: NanoString® nCounter PanCancer Immunity Panel; PBC; Prognosis; Stratification; UDCA