Early Molecular Stratification of High-risk Primary Biliary Cholangitis

• Published in: EBioMedicine 2016-12, Vol.14, p.65-73
• Main Authors: Hardie, Claire, Green, Kile, Jopson, Laura, Millar, Ben, Innes, Barbara, Pagan, Sarah, Tiniakos, Dina, Dyson, Jessica, Haniffa, Muzlifah, Bigley, Venetia, Jones, David E, Brain, John, Walker, Lucy J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomarkers; Biopsy; Cholangitis - genetics; Cholangitis - metabolism; Cholangitis - pathology; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Disease Progression; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Male; Middle Aged; NanoString® nCounter PanCancer Immunity Panel; PBC; Prognosis; Research Paper; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stratification; Transcriptome; UDCA
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2016.11.021

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. •30% of PBC patients have high-risk disease defined after a year of non-response to ursodeoxycholic acid therapy.•Gene-expression profiles from FFPE archival index liver biopsies demonstrate distinct clustering of high- and low-risk PBC.•High-risk genes are linked to T-cell activation, apoptosis, migration; IFN-γ signalling; and biliary senescence.•The risk ‘signal’, detectable from FFPE liver biopsy samples, has potential utility as a clinical diagnostic tool. PBC is a chronic disease causing injury to bile ducts within the liver. 70% of patients have low-risk PBC and respond to treatment. The remaining 30% have un-responsive, high-risk disease that can progress to cirrhosis, liver-failure and the need for liver transplantation. Currently high-risk disease is only determined after a year of treatment failure. This study demonstrates that genes expressed in liver biopsies taken at diagnosis from patients with PBC allow high-risk disease to be identified earlier and this could