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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Familial Cancer, BRCA1-Associated Protein-1 (BAP1) Mutations, Tumor Predisposition Syndrome (TPDS), Mesothelioma

Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cancer patients<br>Individuals with history of cancer and detected or suspected germline mutation in BAP1 TPDS | |
| Relatives of cancer patients<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Genetics, Germline Mutation in the BAP1 Gene, BRCA1-Associated Protein-1, Familial Background, Natural History, DECT