Abstract 2276: High frequency of pathogenic germline variants in patients with malignant mesothelioma
Authors: Belcaid Laila , Bertelsen Birgitte , Wadt Karin A. , Tuxen Ida V. , Spanggaard Iben , Højgaard Martin , Sørensen Jens B. , Lassen Ulrik , Nielsen Finn C. , Rohrberg Kristoffer , Yde Christina W. 
Published: June 2022

Abstract
Background: Malignant mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification and characterization of germline variants in malignant mesothelioma is relevant for identifying potential actionable targets and genetic counseling of family members.
Methods: Patients referred to the Phase I Unit at Rigshospitalet were prospectively enrolled into the Copenhagen Prospective Personalized Oncology trial and underwent whole exome sequencing for somatic and germline variants. Between January 2014 and September 2021, 45 patients with MM were identified and 40 patients underwent whole exome sequencing. Germline variants were selected according to association to inherited cancer using a 168-gene panel and variants were classified according to ACMG/AMP classification as pathological (class 5) or likely pathogenic (class 4).
Results: 34 males (85%) and 6 females (15%) with a median age of 64 years (range: 43-77) were available for analysis. The majority (85%) had malignant pleural mesothelioma whilst the rest (15%) had malignant peritoneal mesothelioma. Histological subtypes were distributed between epithelioid type (N=24, 60%), biphasic type (N=12, 30%) and the sarcomatoid type (N=4, 10%).
A pathogenic or likely pathogenic variant was found in 16 patients (40%). In total 13 different germline variants were identified (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The variants included five frameshifts (33%), four missenses (25%), four nonsenses (25%), one splice site (6%), one start loss (6%) and one synonymous (6%).
The pathogenic germline variants were found in DNA repair pathways, including homologous recombination repair (69%), nucleotide excision repair (13%), cell cycle regulatory (6%), DNA damage checkpoint control (6%) and hypoxic pathway (6%). Three (19%) of the patients with a germline variant had a second cancer. A previously undiagnosed BRCA2 germline mutation was found in 2 patients. A potential treatment target based on the pathogenic germline variant could be suggested in four patients (10%).
Conclusion: The current analysis revealed a high frequency of pathogenic germline variants in patients with malignant mesothelioma. These data support germline testing in these patients and provide a rationale for additional investigation of the homologous recombination pathway as a potential target for precision medicine.
Citation Format: Laila Belcaid, Birgitte Bertelsen, Karin A. Wadt, Ida V. Tuxen, Iben Spanggaard, Martin Højgaard, Jens B. Sørensen, Ulrik Lassen, Finn C. Nielsen, Kristoffer Rohrberg, Christina W. Yde. High frequency of pathogenic germline variants in patients with malignant mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2276.