Genetic Susceptibility in MAlignant Pleural Mesothelioma: Clinical Implication of GermliNE VariaTionS

NCT06886672 | Recruiting

• 1 other identifier: MAGNETS
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 2

Brief Summary

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural mesothelium, mainly associated to asbestos exposure, still lacking effective therapies. Asbestos is a not-mutagenic agent: its nanosized fibres directly interact with tyrosine kinases (TKs) (e.g. EGFR) and may induce inappropriate receptor dimerization and activation, in absence of activating somatic mutations. TK receptor activation initiates cell signaling cascades and carcinogenesis. Asbestos, thus, induces the generation of an inflammatory immunosuppressive microenvironment that may support tumor growth in individuals with genetic predisposition (2). Consequently, the lack of actionable tumor targets together with the heterogeneous stroma, support the failure of modern drugs, both TK and immune-checkpoint inhibitors (TKIs, ICIs). In this complex context, the role of germline changes in MPM remains largely unexplored, except for changes in the BAP1 gene which are known to predispose to the disease (3). The main goal of the study is to look for germline changes of a panel of genes involved in microenvironment infiltration modulation, drug response and cancer predisposition. The study will be performed in parallel on blood samples obtained from asbestos-exposed subjects and on MPM patients. This approach will allow: detection of putative germline signatures associated with MPM onset predisposition (or even protection) with prognostic and predictive implications. The genetic characterization of MPM has not been fully clarified until now due to the significant inter-patient variability and to the scarcely reported somatic aberrations. Most of genetic alterations in MPM are loss of function of tumor suppressor genes or caretaker genes. Thus, the present project aimed at deeply investigate the germline variation in MPM and exposed population to determine host factors involved in MPM promotion. Pathogenic germline variants in MPM are often involved in DNA damage repair and chromatin remodeling pathways, and the most frequently identified germline mutations are in BAP1 which encodes for a tumor suppressor gene. Its protein is a nuclear deubiquitinating enzyme that plays an important role in chromatin modulation, transcriptional regulation, cell proliferation, DNA repair, cell death, and glucidic metabolism. Based on systematic literature review performed to identify all relevant data, a set of 30 genes involved in microenvironment infiltration modulation (e.g. RBL1), drug response (e.g. XRCC1) and cancer predisposition (e.g. BRAC1-2) has been defined. This phase will encompass a first step focused on deep mutational screening aimed at analyzing a custom panel of genes involved in microenvironment immune-inflammatory on peripheral blood mononuclear cell (PBMC)-derived DNA. A next-generation sequencing (NGS) approach will be applied by Illumina-iSeq 100 Sequencing System. From each subject enrolled in this study, total DNA will be extracted by automated purification system, then 20 ng of input DNA will be used for library construction and next generation sequencing of all coding exons from cancer related gene. The identified variants will be submitted to bioinformatics analysis by PolyPhen-2, SIFT and Ensembl Variant Effect Predictor (VEP), to assess the possible impact of the corresponding amino acid substitution on the structure and function of the encoded protein. In addition, clinically significant variants will be annotated by using ClinVar-NCBI, GnomAD and COSMIC databases. Recent clinical studies have associated high tumor mutational burden (TMB) with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. Moreover, it has been shown that germline variants can influence the molecular phenotypes of tumors and thus predict the checkpoint inhibitors efficacy. Staring from these considerations, in this study we will also analyze the germline tumor mutational burden (gTMB) by assessing the total number of nonsynonymous mutations in each selected gene.

Conditions

Mesothelioma, Malignant Pleural

Keywords

MPM; germline mutations; asbestos exposure

Outcome Measures

Primary Outcomes (1)

• the comparison of prevalence of germline mutations in MPM patients vs asbestos exposed healthy subjects

  From each subject enrolled, DNA will be extracted by automated purification system. 20ng of input DNA will be used for library construction and next generation sequencing of all coding exons from cancer related gene. The identified variants will be submitted to bioinformatics analysis by PolyPhen-2, SIFT and Ensembl Variant Effect Predictor, to assess the possible impact of the corresponding amino acid substitution on structure and function of the encoded protein. Clinically significant variants will be annotated using ClinVar-NCBI, GnomAD, COSMIC databases. Recent studies have associated high tumor mutational burden with improved patient response rates and survival benefit from immune checkpoint inhibitors. It has been shown that germline variants can influence the molecular phenotypes of tumors and thus predict the checkpoint inhibitors efficacy. We will analyze the germline tumor mutational burden by assessing the total number of nonsynonymous mutations in each selected gene.

  At enrollment visit 4mL whole blood will be collected by blood draw

Secondary Outcomes (1)

• Secondary aim will be the comparison of overall survival (OS) according to mutational status in MPM patients.

  From enrollment until 12 months, or until the participant is lost to follow-up

Study Arms (2)

Cohort A

patients affected by MPM

Cohort B

asbestos exposed subjects

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Two different study populations will be candidate to the study: Cohort A- patients affected by MPM, followed in the Pneumology Units (IRCCS Policlinico San Matteo Foundation and Oncology Unit at ICS Maugeri IRCCS); Cohort B- asbestos exposed subjects, followed in the Occupational Hospital Medicine Unit (UOOML) at ICS Maugeri IRCCS.

You may qualify if:

• Patient with a documented diagnosis of MPM (any disease stage and independently from chemo line treatment)
• Age ≥ 18 years (there is no upper age limit).
• Patient who gives their informed consent to participate in the study

You may not qualify if:

• Former asbestos exposed healthy subjects
• Age ≥ 18 years (there is no upper age limit).
• Subject who gives their informed consent to participate in the study

Sponsors & Collaborators

• Fondazione IRCCS Policlinico San Matteo di Pavia: lead
• Istituti Clinici Scientifici Maugeri di Pavia: collaborator

Study Sites (2)

Fondazione IRCCS Policlinico San Matteo

Pavia, Pavia, 27100, Italy

RECRUITING

IRCCS Istituti Clinici Maugeri, Medicina del Lavoro

Pavia, Pavia, 27100, Italy

RECRUITING

Related Publications (3)

• Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox NJ, Dogan AU, Pass HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, Carbone M. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011 Aug 28;43(10):1022-5. doi: 10.1038/ng.912.

  PMID: 21874000 BACKGROUND

• Lettieri S, Bortolotto C, Agustoni F, Lococo F, Lancia A, Comoli P, Corsico AG, Stella GM. The Evolving Landscape of the Molecular Epidemiology of Malignant Pleural Mesothelioma. J Clin Med. 2021 Mar 3;10(5):1034. doi: 10.3390/jcm10051034.

  PMID: 33802313 BACKGROUND

• Roe OD, Stella GM. Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic. Eur Respir Rev. 2015 Mar;24(135):115-31. doi: 10.1183/09059180.00007014.

  PMID: 25726562 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

whole blood

MeSH Terms

Conditions

Mesothelioma, Malignant

Condition Hierarchy (Ancestors)

Mesothelioma; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases

Central Study Contacts

Giulia Maria Stella, MD

CONTACT

+390382503369; g.stella@smatteo.pv.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: March 6, 2025
• First Posted: March 20, 2025
• Study Start: June 15, 2023
• Primary Completion: February 28, 2025
• Study Completion: December 31, 2025
• Last Updated: March 20, 2025

Record last verified: 2025-02

Locations

IT (2)