Molecular characterization of pleomorphic mesothelioma: a multi-institutional study

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.