Clinical trial NCT06777914: Familial Intrahepatic Cholestasis-related Genes Associated with Disease Susceptibility in Hepato-biliary Cancers
Official title: Familial Intrahepatic Cholestasis-related Genes Associated with Disease Susceptibility in Hepato-biliary Cancers
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Hepatobiliary Cancers
Progressive Familial Intrahepatic Cholestasis (PFIC)
Cholestatic Liver Disease
Lead sponsor: IRCCS Azienda Ospedaliero-Universitaria di Bologna
Sponsor class: OTHER
First posted: 2025-01-16
Enrollment: 600
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: OTHER
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.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Prevalence of Pathogenic and Variant Mutations in PFIC Genes in HBCs and CCLDs Patients
timeFrame: 3 years
Secondary outcomes:
measure: Identifying New PFIC-Associated Genes in HBCs and CCLDs Patients Negative for NGS Analysis via WES
timeFrame: 3 years
measure: Identification of Somatic Mutations in Tumor Tissue Samples from Patients Undergoing Liver Resection or Transplantation for HBCs
timeFrame: 3 years
measure: Laboratory and Clinical Features of HBCs and CCLDs Patients
timeFrame: 3 years
measure: Comparison of Allelic Frequency of PFIC-Related Mutations in the NGS Panel between the Study Population and gnomAD Database
timeFrame: 3 years
Other outcomes:
Locations:
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna - Programma Chirurgia addominale nell'insufficienza d'organo terminale e nei pazienti con trapianto d'organo
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna - UO Chirurgia Epatobiliare e dei Trapianti
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna - UO Gastroenterologia
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna - UO Medicina Interna per il trattamento delle gravi insufficienze d'organo
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna - UO Medicina Interna, malattie epatobiliari e immunoallergologiche
Study officials:
affiliation: IRCCS Azienda Ospedaliero-Universitaria di Bologna
name: Giovanni Vitale, MD
role: PRINCIPAL_INVESTIGATOR
References: