Genomic Landscape of Pleural and Peritoneal Mesothelioma Tumors

Hiltbrunner, Stefanie; Fleischmann, Zoë; Sokol, Ethan S.; Zoche, Martin; Felley-Bosco, Emanuela; Curioni-Fontecedro, Alessandra

doi:10.2139/ssrn.4060087

Cited by 2 publications

(7 citation statements)

References 36 publications

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“…Besides a predisposition for mesothelioma, these patients are also commonly affected by BAP1 -inactivated melanocytic tumors, uveal melanoma, cutaneous melanoma and renal cell carcinoma [ 31 ]. In line with other studies, we found oncogenic BAP1 mutations in 32% of tumors in the current cohort, of which two patients were known carriers of a BAP1 germline mutation [ 7 , 10 , 11 ]. BAP1 encodes for the tumor suppressor protein ‘ubiquitin carboxyl-terminal hydrolase,’ which plays a role in several cellular processes involved in oncogenesis [ 32 ].…”

Section: Discussionsupporting

confidence: 93%

“…Inactivating mutations of NF2 lead to cell cycle progression and cell proliferation [ 45 , 46 ]. NF2 mutations are reported by previous studies in around 25% of cases of PeM [ 10 , 11 ]. Some clinical studies and some preclinical evidence suggest that NF2 inactivation might be associated with response to mTOR inhibitors.…”

Section: Discussionmentioning

confidence: 90%

“…Although also rare, pleural mesothelioma is relatively more common and treatment strategies for PeM are commonly derived from the pleural variant. Recently, large cohorts of both pleural and PeM have provided more insights in their mutational profiles and provided possible targets or therapies [ 7 – 11 , 18 ]. The mutational profile of the current study cohort is comparable to the TCGA pleural mesothelioma cohort, which is in line with the large cohorts of Hiltbrunner et al and Dagogo-Jack et al [ 10 , 11 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…There are some studies that reported MSI in patients with mesothelioma, but these cases are rare [ 10 , 24 ]. With regard to TMB, several studies reported low TMB in the majority of mesothelioma cases (both pleural and peritoneal) [ 10 , 11 , 25 ]. As both MSI and high-TMB tumors are associated with a good response to immune checkpoint inhibition (CPI) therapy, one might expect that these therapies are ineffective against mesothelioma [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, data on the mutational landscape of PeM have long been lacking. Recently, several studies have been published that provide more insights in the mutational profile of PeM [ 7 – 11 ]. These data could aid to identify new treatment options for patients with PeM.…”

Section: Introductionmentioning

confidence: 99%

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Genomic characterization and detection of potential therapeutic targets for peritoneal mesothelioma in current practice

van Kooten,

Dietz,

Dubbink

et al. 2024

Clin Exp Med

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Peritoneal mesothelioma (PeM) is an aggressive tumor with limited treatment options. The current study aimed to evaluate the value of next generation sequencing (NGS) of PeM samples in current practice. Foundation Medicine F1CDx NGS was performed on 20 tumor samples. This platform assesses 360 commonly somatically mutated genes in solid tumors and provides a genomic signature. Based on the detected mutations, potentially effective targeted therapies were identified. NGS was successful in 19 cases. Tumor mutational burden (TMB) was low in 10 cases, and 11 cases were microsatellite stable. In the other cases, TMB and microsatellite status could not be determined. BRCA1 associated protein 1 (BAP1) mutations were found in 32% of cases, cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) and neurofibromin 2 (NF2) mutations in 16%, and ataxia-telangiectasia mutated serine/threonine kinase (ATM) in 11%. Based on mutations in the latter two genes, potential targeted therapies are available for approximately a quarter of cases (i.e., protein kinase inhibitors for three NF2 mutated tumors, and polyADP-ribose polymerase inhibitors for two ATM mutated tumors). Extensive NGS analysis of PeM samples resulted in the identification of potentially effective targeted therapies for about one in four patients. Although these therapies are currently not available for patients with PeM, ongoing developments might result in new treatment options in the future.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genomic characterization and detection of potential therapeutic targets for peritoneal mesothelioma in current practice

van Kooten,

Dietz,

Dubbink

et al. 2024

Clin Exp Med

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Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response

Osmanbeyoglu

Palmer

Sagan

et al. 2022

Cancers

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Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1, CDKN2A/B, and NF2 are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with genomic alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B genomic alterations consistently contributed to an adverse clinical outcome. Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies.

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Genomic Landscape of Pleural and Peritoneal Mesothelioma Tumors

Cited by 2 publications

References 36 publications

Genomic characterization and detection of potential therapeutic targets for peritoneal mesothelioma in current practice

Genomic characterization and detection of potential therapeutic targets for peritoneal mesothelioma in current practice

Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response

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