Mechanisms of Somatic Mutation and Tumor Initiation in Pre-malignant Kidney Tubule Cells (SoMuKT)

The goal of this observational study is to analyze somatic mutations in the genome of normal kidney cells from patients affected by kidney cancer predisposition syndrome Von Hippel Lindau (VHL) and compare the mutation rates observed in these patients and in individuals not affected by the disease. The main questions the study aims to answer are:

• Do kidney cells from VHL patients mutate more than cells from control individuals during adult life?
• What mechanisms favor somatic mutation occurrence in the genome of normal kidney tubule cells?

Participants will donate one blood sample and multiple urine samples. Urines will be used for kidney cell isolation, followed by cell culturing and genetic analyses. Urine samples will be collected once a year for 3-5 years. Sample collection will occur during the yearly screening program that each patient undergoes at the hospital. In case patients undergo surgical treatment of kidney tumors, samples discarded from surgery (tumor and normal kidney adjacent to tumor) will be collected and subjected to genetic analyses.

Researchers will compare the number and types of mutations found in tumors and normal kidney cells from VHL-disease patients with those found in normal kidney cells from control individuals, to see if somatic mutation rates are increased in VHL-disease patients during aging.

Study Overview

• Status: Recruiting
• Conditions: Carcinoma, Renal Cell; Von Hippel-Lindau Disease
• Intervention / Treatment: Other: Blood and urine sample collection

• Study Type: Observational
• Enrollment (Estimated): 50

Contacts and Locations

• Study Contact: Name: Irene Franco, PhD; Phone Number: +39 02 2643 2357; Email: franco.irene@hsr.it
• Study Contact Backup: Name: Daniela Canibus, BsC; Phone Number: +39 02 2643 5628; Email: canibus.daniela@hsr.it

Study Locations

• Italy
  • MIlan, Italy, 20132
    • Recruiting
    • IRCCS Ospedale San Raffaele
    • Contact: Irene Franco, PhD; Phone Number: +39 0226432357; Email: franco.irene@hsr.it
    • Contact: Daniela Canibus, Bsc; Phone Number: +39 0226435628; Email: canibus.daniela@hsr.it

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Patients with genetic diagnosis of VHL-disease, between 25 and 65, both genders

Description

Inclusion Criteria:

• Genetic diagnosis of VHL-disease; age (data need to be collected from a population distributed between 25 and 65 years); gender (males and females should be equally represented);

Exclusion Criteria:

• patients with bilateral nephrectomy, in dialysis or kidney transplant; use of nephrotoxic drugs

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Controls; Healthy volunteers; patients referring to San Raffaele Hospital for renal/urological conditions other than VHL	Other: Blood and urine sample collection; One whole blood sample per individual (3 ml) will be collected. Up to 5 urine samples per individual will be collected
VHL-disease patients; Individuals with genetic diagnosis of Von Hippel Lindau disease	Other: Blood and urine sample collection; One whole blood sample per individual (3 ml) will be collected. Up to 5 urine samples per individual will be collected

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of somatic mutation accumulation in normal kidney tubule genomes	The genome of multiple normal kidney cells from each subject will be investigated by whole genome sequencing. The number of somatic mutations per genome will be plotted according to donor's age and a curve describing the accumulation of mutations with age will be obtained for both the control and VHL-disease patient populations. The aim is to assess differences in mutation rates in the kidney of VHL-disease patients vs controls and understand the underlying mechanism.	Normal kidney tubule cells from urines are assessed from control and VHL-disease patients typically over a period of 3 years (min 3 months, max 3 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of pre-cancer cells in urines	From each urine sample, researchers can culture up to 20 single cell clones and perform a single-clone, gene-expression analysis. The expression of markers that characterize the mutation-prone, pre-cancer population will be assessed in all clones. The fraction of clones expressing markers of pre-cancer cells will be calculated in control and VHL-disease groups. The aim is to assess any differences in the presence of pre-cancer cells in urines from VHL-disease patients vs controls and assess any correlation of this parameter with kidney cancer occurrence.	Normal kidney tubule cells from urines are assessed from control and VHL-disease patients typically over a period of 3 years (min 3 months, max 3 years)

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Collaborators: Università Vita-Salute San Raffaele
• Investigators: Principal Investigator: Irene Franco, PhD, IRCCS Ospedale San Raffaele; Principal Investigator: Alessandro Larcher, MD, IRCCS Ospedale San Raffaele; Study Chair: Andrea Salonia, MD, IRCCS Ospedale San Raffaele

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2023
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: December 22, 2023
• First Submitted That Met QC Criteria: December 22, 2023
• First Posted (Actual): January 8, 2024

Study Record Updates

• Last Update Posted (Actual): January 10, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Whole genome sequencing; Somatic mutations; Normal kidney
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Congenital Abnormalities; Genetic Diseases, Inborn; Kidney Neoplasms; Abnormalities, Multiple; Neurocutaneous Syndromes; Ciliopathies; Angiomatosis; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Precancerous Conditions; Von Hippel-Lindau Disease
• Other Study ID Numbers: SoMuKT

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No