The molecular alterations of pleomorphic mesotheliomas are largely unknown. In the present study, we performed whole-exome sequencing (WES) on 24 pleomorphic mesotheliomas in order to better characterize the molecular profile of this rare histologic variant. BAP1 protein expression and CDKN2A deletion by FISH were also evaluated. Significantly mutated genes included BAP1 (35%), NF2 (13%), LATS2 (8%), TP53 (5%), and LATS1 (3%). BAP1 alterations most frequently co-occurred with deletions of chromosomes 4, 9, and 13. Other important genetic alterations in pleomorphic mesotheliomas included truncating mutations in NF2 (3 of 24; 12.5%), LATS2 (2 of 24; 8%), TP53 (1 of 24; 4%), and PBRM1 (1 of 24; 4%). Focal losses of chromosome 9p21 were most common copy number alterations (11 of 24 cases; 46%), and were assessed by WES and targeted FISH. The second most common were deletions of chromosome 4 (8 of 24; 33% pleomorphic mesotheliomas). Three cases of pleomorphic mesothelioma did not show any mutations, copy number alterations, or LOH. This first WES analysis of pleomorphic mesotheliomas did not identify novel or unique mutations. In contrast to transitional mesothelioma that was reclassified as sarcomatoid variant based on transcriptome data, pleomorphic mesotheliomas are molecularly heterogeneous and therefore their reclassification into single subtype is more difficult.
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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Sauter, J. L., Bueno, R., Dacic, S. in The WHO Classification of Tumours Editorial Board. WHO Classification of Tumours 5th edition Thoracic Tumours 209–217 (IARC Press, 2021).
Meyerhoff, R. R. et al. Impact of mesothelioma histologic subtype on outcomes in the Surveillance, Epidemiology, and End Results database. J. Surg. Res. 196, 23–32 (2015).
Kindler, H. L. et al. Treatment of malignant pleural mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 36, 1343–1373 (2018).
Husain, A. N. et al. Guidelines for pathologic diagnosis of malignant mesothelioma 2017 update of the consensus statement from the International Mesothelioma Interest Group. Arch. Pathol. Lab. Med. 142, 89–108 (2018).
Kadota, K. et al. Pleomorphic epithelioid diffuse malignant pleural mesothelioma: a clinicopathological review and conceptual proposal to reclassify as biphasic or sarcomatoid mesothelioma. J. Thorac. Oncol. 6, 896–904 (2011).
Brcic, L., Vlacic, G., Quehenberger, F. & Kern, I. Reproducibility of malignant pleural mesothelioma histopathologic subtyping. Arch. Pathol. Lab. Med. 142, 747–752 (2018).
Bilecz, A. et al. Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma. Histopathology 77, 55–66 (2020).
Galateau Salle, F. et al. Comprehensive molecular and pathologic evaluation of transitional mesothelioma assisted by deep learning approach: a multi-institutional study of the International Mesothelioma Panel from the MESOPATH Reference Center. J. Thorac. Oncol. 15, 1037–1053 (2020).
Li MM, et al. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn 19, 4–23 (2017).
Chevrier, M. et al. Testing for BAP1 loss and CDKN2A/p16 homozygous deletion improves the accurate diagnosis of mesothelial proliferations in effusion cytology. Cancer Cytopathol. 12, 939–947 (2020).
Bueno, R. et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat. Genet. 48, 407–416 (2016).
Hmeljak, J. et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov. 8, 1548–1565 (2018).
Quetel, L. et al. Genetic alterations of malignant pleural mesothelioma: association with tumor heterogeneity and overall survival. Mol. Oncol. 14, 1207–1223 (2020).
Blum, Y. et al. Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Nat. Commun. 10, 1333 (2019).
de Reyniès, A. et al. Molecular classification of malignant pleural mesothelioma: identification of a poor prognosis subgroup linked to the epithelial-to-mesenchymal transition. Clin. Cancer. Res. 20, 1323–1334 (2014).
Galateau Salle, F. et al. New insights on diagnostic reproducibility of biphasic mesotheliomas: a multi-institutional evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center. J Thorac. Oncol. 13, 1189–1203 (2018).
Tranchant, R. et al. Co-occurring mutations of tumor suppressor genes, LATS2 and NF2, in malignant pleural mesothelioma. Clin. Cancer Res. 23, 3191–3202 (2017).
De Rienzo, A. et al. Large-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesothelioma. J. Pathol. 253, 68–79 (2021).
Dacic, S. et al. Whole exome sequencing reveals BAP1 somatic abnormalities in mesothelioma in situ. Lung Cancer 149, 1–4 (2020).
Panou, V. et al. Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma. J. Clin. Oncol. 36, 2863–2871 (2018).
Walpole, S. et al. Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. J. Natl Cancer Inst. 110, 1328–1341 (2018).
López-Ríos, F. et al. Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res. 66, 2970–2979 (2006).
Dacic, S. et al. Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas. Virchows Arch. 453, 627–635 (2008).
Yoshikawa, Y. et al. Frequent deletion of 3p21.1 region carrying semaphorin 3G and aberrant expression of the genes participating in semaphorin signaling in the epithelioid type of malignant mesothelioma cells. Int. J. Oncol. 39, 1365–1374 (2011).
Björkqvist, A. M. et al. Comparison of DNA copy number changes in malignant mesothelioma, adenocarcinoma and large-cell anaplastic carcinoma of the lung. Br. J. Cancer 77, 260–269 (1998).
Bjorkqvist, A. M., Tammilehto, L., Anttila, S., Mattson, K. & Knuutila, S. Recurrent DNA copy number changes in 1q, 4q, 6q, 9p, 13q, 14q and 22q detected by comparative genomic hybridization in malignant mesothelioma. Br. J. Cancer 75, 523–527 (1997).
Shivapurkar, N. et al. Deletions of chromosome 4 at multiple sites are frequent in malignant mesothelioma and small cell lung carcinoma. Clin. Cancer Res. 5, 17–23 (1999).
The authors would like to thank all the Experts of the MESOPATH College: G. Averous, H. Begueret, E. Brambilla, M. Brevet, F. Capron, A. Cazes, L. Chalabreysse, M.C. Copin, D. Damotte, C. Danel, P. Dartigues, A.Y. De Lajartre, J. Fontaine, A. Foulet-Roge, L. Garbe, S. Giusiano-Courcambeck, O. Groussard, V. Hofman, S. Humez, S. Isaac, S. Lantuejoul, E. Mery, J.M. Picquenot, N. Piton, G. Planchard, I. Rouquette, P. Rouvier, C. Sagan, F. Thivolet, S. Valmary, and J.M. Vignaud.
This work and the International Mesothelioma Panel were supported by The French National Cancer Institute core grant and the French Health National Institute Santé Publique France since 1998. This study was supported by research funds of the Department of Pathology University of Pittsburgh Medical Center.
The authors declare no competing interests.
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The study protocol was reviewed and approved by the institutional review board of the University of Pittsburgh (PRO18010420).
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Roy, S., Galateau-Sallé, F., Le Stang, N. et al. Molecular characterization of pleomorphic mesothelioma: a multi-institutional study. Mod Pathol (2021). https://doi.org/10.1038/s41379-021-00900-z