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

• Published in: Cancers Vol. 12; no. 9; p. 2454
• Main Authors: Torricelli, Federica, Lococo, Filippo, Di Stefano, Teresa Severina, Lorenzini, Eugenia, Piana, Simonetta, Valli, Riccardo, Rena, Ottavio, Veronesi, Giulia, Billè, Andrea, Ciarrocchi, Alessia
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 29.08.2020; MDPI
• Subjects: Asbestos; Cancer therapies; Chemotherapy; DNA sequencing; Gene amplification; Gene mutation; Genetic analysis; Genetic aspects; genetic mutations; Health aspects; histotype; Malignant Pleural Mesothelioma; Medical prognosis; Mesothelioma; Methods; Mutation; next generation sequencing; NOD2 protein; Ostomy; Patients; Phenotypes; Sequence analysis; Surgery; United States
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12092454

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.