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Early Molecular Stratification of High-risk Primary Biliary Cholangitis

Lookup NU author(s): Kile Green, Dr Laura Jopson, Dr Ben Millar, Barbara Innes, Sarah Pagan, Dr Dina Tiniakos Tiniakos, Dr Jess Dyson, Professor Muzlifah Haniffa, Dr Venetia Bigley, Professor David Jones, Dr John Brain, Dr Lucy Walker

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2016 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.


Publication metadata

Author(s): Hardie C, Green K, Jopson L, Millar B, Innes B, Pagan S, Tiniakos D, Dyson J, Haniffa M, Bigley V, Jones DE, Brain J, Walker LJ

Publication type: Article

Publication status: Published

Journal: EBioMedicine

Year: 2016

Volume: 14

Pages: 65-73

Print publication date: 01/12/2016

Online publication date: 21/11/2016

Acceptance date: 16/11/2016

ISSN (electronic): 2352-3964

Publisher: Elsevier B.V.

URL: https://doi.org/10.1016/j.ebiom.2016.11.021

DOI: 10.1016/j.ebiom.2016.11.021

PubMed id: 27913155


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