New pathogenic germline variants identified in mesothelioma

Laila Belcaid*, Birgitte Bertelsen, Karin Wadt, Ida Tuxen, Iben Spanggaard, Martin Højgaard, Jens Benn Sørensen, Jesper Ravn, Ulrik Lassen, Finn Cilius Nielsen, Kristoffer Rohrberg, Christina Westmose Yde

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftReviewForskningpeer review

1 Citationer (Scopus)
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Abstract

Background: Mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification of germline pathogenic variants (PVs) in mesothelioma is relevant for identifying potential actionable targets and genetic counseling. Methods: 44 patients underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Germline variants were selected according to association with inherited cancer using a 168-gene in silico panel, and variants classified according to ACMG/AMP classification as pathogenic (class 5) or likely pathogenic (class 4). Results: In total, 16 patients (36%) were found to carry pathogenic or likely pathogenic variants in 13 cancer associated genes (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The germline PVs occurred in DNA repair pathways, including homologous recombination repair (HRR) (75%), nucleotide excision repair (6%), cell cycle regulatory (7%), base excision repair (6%), and hypoxic pathway (6%). Five (31%) patients with a germline PV had a first or second degree relative with mesothelioma compared to none for patients without a germline PV. Previously undiagnosed BRCA2 germline PVs were identified in two patients. Potential actionable targets based on the germline PVs were found in four patients (9%). Conclusion: This study revealed a high frequency of germline PVs in patients with mesothelioma. Furthermore, we identified germline PVs in two genes (NBN & RAD51B) not previously associated with mesothelioma. The data support germline testing in mesothelioma and provide a rationale for additional investigation of the HRR pathway as a potential actionable target.

OriginalsprogEngelsk
Artikelnummer107172
TidsskriftLung Cancer
Vol/bind179
Antal sider8
ISSN0169-5002
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
The authors thank all the patients and their relatives for the participation. Conduction of this study would not have been possible without the work of the Kennedy Center and its laboratory staff at Glostrup, Denmark.

Publisher Copyright:
© 2023 The Author(s)

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