Prospective Evaluation of High Resolution Dual Energy Computed Tomographic Imaging, Noninvasive (Liquid) Biopsies, and Minimally Invasive Surgical Surveillance for Early Detection of Mesotheliomas in Patients With BAP1 Tumor Predisposition Syndrome

Background:

A germline mutation is a change to a person s genes that is carried through their DNA. These mutations can be passed on from parents to their offspring. Germline mutations in a gene called BAP1 are linked to the development of mesothelioma and other cancers. Researchers want to follow people with these mutations to learn more.

Objective:

To see if researchers can improve how people who have or are suspected to have a BAP1 mutation are monitored over time.

Eligibility:

People age 30 and older who are suspected to have a BAP1 germline mutation.

Design:

Participants will be screened with a personal and family medical history. Their medical records may be reviewed. They will give a blood or saliva sample to test for a BAP1 mutation. They will get genetic counseling.

To take part in this study, participants will enroll on 2 to 3 other protocols.

Participants will have a physical exam. They may have a tumor biopsy. They will give blood and urine samples. They will have skin and eye exams.

Some participants will have video-assisted thoracoscopy to examine the chest and lungs and diagnose suspicious areas. For this, a small camera is inserted into the chest through a small incision.

Some participants will have laparoscopy to examine the organs inside the abdomen. For this, a small camera is inserted into the abdomen through a small incision.

Participants will have imaging scans of the chest, abdomen, and pelvis. They may have brain scans.

Participants will visit the NIH once a year for follow-up exams.

Participation lasts indefinitely.

Study Overview

• Status: Recruiting
• Conditions: Mesothelioma; Familial Cancer; BRCA1-Associated Protein-1 (BAP1) Mutations; Tumor Predisposition Syndrome (TPDS)

Detailed Description

Background:

• Mutations involving BRCA1-Associated Protein-1 (BAP1), a nuclear deubiquitinase involved in epigenetic regulation of gene expression, DNA repair, and cellular energetics, have emerged as one of the most common somatic mutations in malignant mesotheliomas.
• Germline mutations involving BAP1 predispose individuals to mesothelioma as well as a variety of other malignancies including melanoma and lung, renal, gastric, breast, and biliary tract cancers.
• The cancer penetrance of germline BAP1 mutations is nearly 100%, with most patients developing multiple neoplasms.
• Presently there are no established guidelines for surveillance of cancer patients with germline BAP1 mutations or of cancer-free individuals with germline BAP1 mutations.

Objectives:

To prospectively gather information related to the use of dual energy computed tomographic imaging (DECT), together with minimally invasive surgical surveillance for early detection of pleural or peritoneal mesothelioma in patients with BAP1 tumor predisposition syndrome (TPDS)

Eligibility:

• Individuals with a history of any malignancy with known or suspected germline mutation involving BAP1.
• First- or second-degree relatives of patients with documented germline BAP1 mutations, who are also found to carry similar germline mutations.
• Age greater than or equal to 30

Design:

• Individuals with suspected hereditary tumor predisposition syndromes will undergo germline evaluation using CLIA-certified next-gen sequencing (NGS).
• First- and second-degree relatives of patients with germline BAP1 mutations will be offered similar NGS evaluation.
• Subjects with germline mutations in BAP1, will undergo periodic dual energy CT (DECT) scans of the chest, abdomen, and pelvis. Plasma cell-free DNA (cfDNA) will be assessed at similar intervals, and minimally invasive surveillance procedures (i.e., video- assisted thoracoscopy and laparoscopy) will be performed periodically to detect early, subclinical malignancies that may be amenable to potentially curative local interventions.

• Study Type: Observational
• Enrollment (Estimated): 800

Contacts and Locations

• Study Contact: Name: David S Schrump, M.D.; Phone Number: (240) 760-6239; Email: david_schrump@nih.gov
• Study Contact Backup: Name: Deneise Francis, R.N.; Phone Number: (240) 858-3974; Email: deneise.francis@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office; Phone Number: 888-624-1937

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Individuals, and family members of the individual, who fulfill clinical criteria of a history of cancer and detected or suspected germline mutation in BAP1 TPDS.

Description

• ELIGIBILITY CRITERIA:

Inclusion Criteria for Genetic Testing

-Eligible individuals include:

--Individuals with a history of any malignancy with known or suspected germline mutations involving BAP1

OR

--First- or second-degree relatives of patients (with or without cancer) with documented BAP1 tumor predisposition syndrome (TPDS).

• Age greater than or equal to 30 years.
• All participants must understand and be willing to sign a written informed consent document.

Inclusion Criteria for Surveillance

-Eligible individuals include those who completed step 1 genetic testing with study-confirmed BAP1 or other germline

TPDS mutation.

-Completed co-enrollment on protocol 06C0014, "Prospective Evaluation of Genetic and Epigenetic Alterations in Patients with Thoracic Malignancies."

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Cancer patients; Individuals with history of cancer and detected or suspected germline mutation in BAP1 TPDS
Relatives of cancer patients; First- or second-degree relatives of a cancer patient (with or without cancer) with documented BAP1 tumor predisposition syndrome (TPDS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prospectively gather information related to the use of dual energy computed tomographic imaging (DECT) together with minimally invasive surveillance for early detection of mesotheliomas in patients with BAP1 TPDS	Documentation of the counts, incidence, and frequencies of cancers from dual energy computed tomographic imaging and minimally invasive surveillance results will be analyzed for statistical analysis for the early detection of mesotheliomas in patients with BAP1 TPDS.	annual or biennial follow-up, 5 years interim analysis

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To characterize the epigenetic features of mesotheliomas associated with germline mutations in BAP1	Characterization of the epigenetic features of mesotheliomas associated with germline mutations in BAP1.	at clinical visits, annual or bi-annual follow-up
To investigate the biological mechanisms associated with prolonged survival in participants with mesothelioma that carry germline BAP1 mutations	Tumor tissue, blood, saliva, or buccal swab specimen for genetic analyses including WES, FACS, Western blots, and RNA sequencing.	once during follow-up per participant agreement

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: David S Schrump, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2021
• Primary Completion (Estimated): June 30, 2038
• Study Completion (Estimated): June 30, 2038

Study Registration Dates

• First Submitted: June 12, 2020
• First Submitted That Met QC Criteria: June 13, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 15, 2024

More Information

Terms related to this study

• Keywords: Genetics; Natural History; Familial Background; Germline Mutation in the BAP1 Gene; BRCA1-Associated Protein-1; DECT
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Disease; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Syndrome; Disease Susceptibility; Mesothelioma; Mesothelioma, Malignant
• Other Study ID Numbers: 200106; 20-C-0106

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: .All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely.@@@@@@Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Genomic data are made available via dbGaP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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