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Integrative molecular characterisation of malignant pleural mesothelioma
Malignant pleural mesothelioma (MPM) is a rare and lethal cancer associated to asbestos exposure. Currently, the pemetrexed and cisplatin combination chemotherapy remains the only approved treatment. In the last 5 years, a growing knowledge on mesothelioma pathobiology has translated into the development of multiple novel therapeutic strategies.1 One of the largest reports of comprehensive genomic profiling of MPM was conducted by Bueno and colleagues. Using RNA-seq data, they identified four distinct molecular subtypes, and through exome analysis, they found that BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 were significantly mutated.2 In an article recently published in Cancer Discovery, Hmeljak and colleagues3 report on a genomic study of 74 MPM samples as part of The Cancer Genome Atlas where they performed a comprehensive molecular profiling, including whole-exome sequencing (WES), copy-number arrays, mRNA sequencing, non-coding RNA expression, DNA methylation and proteomic data.
Some interesting observations derive from their work. Using WES, the authors report a low tumour mutational burden (TMB) with <2 non-synonymous mutations per megabase in all but one sample which places mesothelioma at the low bottom of TMB among cancers. A low TMB may represent a negative predictive biomarker for immunotherapy. However, TMB may have been underestimated as recent studies have revealed that minute deletions are frequent in mesothelioma and are often missed by the approaches used in this study.4 Moreover, an interesting finding of this work is a strong expression of the immune-checkpoint gen VISTA in epitheloid MPM, on the tumour cells themselves. It remains to be seen if this finding will translate into a valuable clinical target for emerging anti-VISTA therapy.
The authors confirm that, from a genomic standpoint, mesothelioma is characterised by a preponderance of tumour suppressor alterations. Indeed, they …
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