New pathogenic germline variants identified in mesothelioma
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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New pathogenic germline variants identified in mesothelioma. / Belcaid, Laila; Bertelsen, Birgitte; Wadt, Karin; Tuxen, Ida; Spanggaard, Iben; Højgaard, Martin; Sørensen, Jens Benn; Ravn, Jesper; Lassen, Ulrik; Nielsen, Finn Cilius; Rohrberg, Kristoffer; Westmose Yde, Christina.
I: Lung Cancer, Bind 179, 107172, 2023.Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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T1 - New pathogenic germline variants identified in mesothelioma
AU - Belcaid, Laila
AU - Bertelsen, Birgitte
AU - Wadt, Karin
AU - Tuxen, Ida
AU - Spanggaard, Iben
AU - Højgaard, Martin
AU - Sørensen, Jens Benn
AU - Ravn, Jesper
AU - Lassen, Ulrik
AU - Nielsen, Finn Cilius
AU - Rohrberg, Kristoffer
AU - Westmose Yde, Christina
N1 - Publisher Copyright: © 2023 The Author(s)
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Cancer genetics
KW - Germline variants
KW - Homologous recombination pathway
KW - Mesothelioma
KW - Precision oncology
U2 - 10.1016/j.lungcan.2023.03.008
DO - 10.1016/j.lungcan.2023.03.008
M3 - Review
C2 - 36944283
AN - SCOPUS:85150153287
VL - 179
JO - Lung Cancer
JF - Lung Cancer
SN - 0169-5002
M1 - 107172
ER -
ID: 366343977