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Molecular characterization of pleomorphic mesothelioma: a multi-institutional study

Abstract

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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Fig. 1: Pleomorphic mesothelioma morphology.
Fig. 2: Ovearll suvival and mesothelioma histology.
Fig. 3: COMUT plot showing gene mutations and copy number alterations of the study mesothelioma cohort.
Fig. 4: Copy number alterations in mesothelioma.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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.

Funding

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.

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S.R., F.G.-S., A.C., R.A., and S.D. performed study concept and design, interpretation of data, writing and review of the paper. N.L.S. provided statistical analysis. M.A.L. provided technical support.

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Correspondence to Sanja Dacic.

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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

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