Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma

Abstract

Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease. Morphologically, three different phenotypes are distinguishable: epithelioid (e-), sarcomatoid (s-) and biphasic (biph-) MPM, the latest, being a mixture of e- and s-MPM cells. Being an intermediate entity, management of biph-MPM, remains debatable and controversial, with different guidelines recommending distinct approaches. Identification of biph-MPM associated genetic alterations, through deep sequencing analysis, may provide useful tools to understand these lesions. A retrospective cohort of 69 surgically resected MPMs, 39 biph-MPMs (56.5%) and 30 e-MPMs (43.5%) was selected. A separate set of 16 biph-MPM was used as validation set. Deep sequencing analysis on an MPM-specific custom panel (MPM_geneset) comprising 1041 amplicons spanning 34 genes was performed. A total of 588 variants and 5309 mutational events were detected. In total, 91.3% of MPMs showed at least one mutation and 76.8% showed co-occurrence of more than one alteration. Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component. Mutations in NOD2 and XRCC6 correlated with patients’ survival. We demonstrated that biph-MPM are associated with a specific mutation set, and that genetic analysis at diagnosis may improve patients’ risk stratification.

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

“…In Torricelli et al. RDX and MXRA5 are present in 42% and 40.6% of the cohort, respectively and authors stated that MXRA5 is specific for the biphasic histotype together with NOD2 ( 143 ). The same genes were also described in the RAMES study where RDX and MXRA5 represented the 42% and 23% of MPMs, respectively, however in this case MXRA5 was identified in both epithelioid and non-epithelioid histotypes ( 144 ).…”

“…Interestingly, the same work reported gene fusions such as EWSR1-ATF1 and FUS-ATF1 and ALK rearrangements that are hardly found in pleural mesothelioma and seem to be specific for young women as compared to ALK-wild type patients but might respond to targeted treatment (127,141,142) (Table 2). Two recent studies have reported novel somatic mutations in RDX and MXRA5 genes, independently (143,144). In Torricelli et al RDX and MXRA5 are present in 42% and 40.6% of the cohort, respectively and authors stated that MXRA5 is specific for the biphasic histotype together with NOD2 (143).…”

The Updating of Biological Functions of Methyltransferase SETDB1 and Its Relevance in Lung Cancer and Mesothelioma

“…H3K9 trimethylation possesses the ability to form heterochromatin, which silences gene transcription and remodels the chromatin structure [ 1 , 9 , 10 ]. Overexpression and downregulation of SETDB1 have been widely found in various cancers, but the detailed mechanisms are still unclear [ 2 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Here, we summarize the biological functions of SETDB1 and its therapeutic relevance in lung cancer and mesothelioma, describing possible diagnostic and therapeutic prospects.…”

Molecular Fingerprints of Malignant Pleural Mesothelioma: Not Just a Matter of Genetic Alterations

“…Morphological grading also offers the best measure of risk stratification of these tumors, being that sarcomatoid the most aggressive and deadly form of MPM. Even if some attempts have been performed [52,53], genetic alterations seem not to account for this diversity. By contrast, hierarchical clustering on the basis of deep gene expression profiling always recapitulates these three categories, with biphasic MPM always in a wide and largely heterogeneous spectrum in between the other two histotypes.…”