Familial Intrahepatic Cholestasis-related Genes Associated with Disease Susceptibility in Hepato-biliary Cancers

This is a cross-sectional, multicenter tissue study with an exploratory aim to estimate the prevalence of genetic mutations that predispose individuals to diseases in the context of cholestatic disorders and hepatobiliary neoplasms. It is intended as a hypothesis-generating study for future empirical investigations.

Study Overview

• Status: Recruiting
• Conditions: Hepatobiliary Cancers; Progressive Familial Intrahepatic Cholestasis (PFIC); Cholestatic Liver Disease

Detailed Description

This is a multicenter, cross-sectional tissue study designed to explore the prevalence of genetic mutations associated with cholestatic liver diseases and hepatobiliary neoplasms. It aims to generate hypotheses for future empirical research.

Patient data will be collected, including medical history, imaging tests (e.g., abdominal ultrasound, CT, and MRI), and liver function tests, along with [BA] levels. Non-invasive liver fibrosis assessment (FibroScan or Shear-Wave elastography) and, where applicable, liver biopsies will be included, all referenced to the time of genetic testing.

Molecular genetic analysis of PFIC will be conducted using a multiplex PCR NGS panel covering 37 genes. If clinical suspicion remains high despite negative NGS results, Whole Exome Sequencing (WES) will be used to identify previously unknown PFIC-related genes. WES will prioritize patients with hepatobiliary cancers on a healthy liver or without advanced fibrosis and those with a family history of PFIC or related conditions.

Variants will be filtered based on clinical significance, gene-disease associations, and functional predictions, using resources like ClinVar, HGMD, and Personal Genomics PGVD. WES analysis will include at least one affected parent when available, with de novo mutations considered when both parents are involved.

Only pathogenic or potentially pathogenic variants will be reported, confirmed by Sanger sequencing. Genetic counseling will be offered for patients with significant findings. Tumor tissue samples will also be analyzed for somatic mutations, potentially guiding therapeutic decisions or family screening.

NGS for somatic mutations will use tumor samples collected for clinical purposes, with findings compared to germline mutations. This may inform treatment options and surveillance protocols for relatives. The data will be stored in an electronic archive using REDCap and analyzed by clinical staff. The collected data will include clinical history, liver function tests, response to ursodeoxycholic acid, liver fibrosis stage, and molecular results, along with relevant family histories and therapies.

For patients undergoing surgery, the data will also cover pre-operative assessments, surgical techniques, and post-operative outcomes.

• Study Type: Observational
• Enrollment (Estimated): 600

Contacts and Locations

• Study Contact: Name: Giovanni Vitale; Phone Number: 051.214.3702; Email: giovanni.vitale@aosp.bo.it

Study Locations

• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna - Programma Chirurgia addominale nell'insufficienza d'organo terminale e nei pazienti con trapianto d'organo
    • Contact: Matteo Ravaioli; Phone Number: 051.214.4810; Email: matteo.ravaioli6@unibo.it
  • Bologna, Italy, 40138
    • Recruiting
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna - UO Chirurgia Epatobiliare e dei Trapianti
    • Contact: Chiara Zanfi; Phone Number: 051.214.4750; Email: chiara.zanfi@aosp.bo.it
  • Bologna, Italy, 40138
    • Recruiting
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna - UO Gastroenterologia
    • Contact: Francesco Azzaroli; Phone Number: 051.214.3888; Email: francesco.azzaroli@unibo.it
  • Bologna, Italy, 40138
    • Recruiting
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna - UO Medicina Interna per il trattamento delle gravi insufficienze d'organo
    • Contact: Giovanni Vitale; Phone Number: 0512143702; Email: giovanni.vitale@aosp.bo.it
  • Bologna, Italy, 40138
    • Recruiting
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna - UO Medicina Interna, malattie epatobiliari e immunoallergologiche
    • Contact: Fabio Piscaglia; Phone Number: 051.214.2568; Email: fabio.piscaglia@unibo.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Subjects with a diagnosis of HBCs who have undergone liver resection or liver transplantation, and a population of patients affected by CCLDs.

Description

Inclusion Criteria:

• Instrumental or histological diagnosis of HBCs, defined as primary liver and/or biliary tumors (hepatocellular carcinoma, cholangiocarcinoma, hepatocholangiocarcinoma) occurring in patients without apparent underlying chronic liver disease or in the context of cryptogenic chronic liver disease;
• Curative treatment through surgical resection of the neoplasm or liver transplantation

• Diagnosis of CCLDs defined as:

  1. GGT and/or alkaline phosphatase >1.5 times the normal values in two or more measurements taken at least 6 months apart,
  2. A history of pruritus combined with [BA] >10 mmol/l for a period of ≥6 months.
• Obtaining written informed consent

Exclusion Criteria:

• Other documented causes of chronic liver disease that can justify the clinical phenotype include:

Primary biliary cholangitis Primary sclerosing cholangitis IgG4-related cholangiopathy Obstructive jaundice excluded by the demonstration of normal bile duct anatomy Negative virological tests for HBV, HCV, HEV Alcohol abuse Hemochromatosis Wilson's disease Alpha-1 antitrypsin deficiency

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of Pathogenic and Variant Mutations in PFIC Genes in HBCs and CCLDs Patients	To estimate the prevalence of pathogenic germline mutations, probably pathogenic mutations, variants of uncertain significance, probably benign variants, and benign variants in the genes responsible for PFIC in individuals diagnosed with HBCs who have undergone liver resection or liver transplantation, and in a population of patients with CCLDs.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identifying New PFIC-Associated Genes in HBCs and CCLDs Patients Negative for NGS Analysis via WES	Estimate the percentage of patients carrying newly identified genes potentially responsible for PFIC, discovered through WES	3 years
Identification of Somatic Mutations in Tumor Tissue Samples from Patients Undergoing Liver Resection or Transplantation for HBCs	Estimate percentage of patients carrying somatic mutations identified through NGS (in PFIC-related genes) or through WES.	3 years
Laboratory and Clinical Features of HBCs and CCLDs Patients	Estimate percentage of patients with PFIC gene mutations and BRIC, LPAC, ICP, DIC phenotype, advanced fibrosis, pruritus, and/or neonatal jaundice	3 years
Comparison of Allelic Frequency of PFIC-Related Mutations in the NGS Panel between the Study Population and gnomAD Database	Estimate the proportion of a specific allele among the total alleles identified in the NGS genetic analysis.	3 years

Collaborators and Investigators

• Sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
• Investigators: Principal Investigator: Giovanni Vitale, MD, IRCCS Azienda Ospedaliero-Universitaria di Bologna

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2024
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: December 3, 2024
• First Submitted That Met QC Criteria: January 10, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 10, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Liver Diseases; Cholestasis; Disease Susceptibility; Cholestasis, Intrahepatic
• Other Study ID Numbers: HBCs-PFIC; RC-2024-2790618 (Other Grant/Funding Number: Ricerca Corrente 2024 - Ministero della Salute)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No