Genomic Landscape of Malignant Mesotheliomas

Molecular Cancer Therapeutics 2016 August 9 [Epub ahead of print] [Link]

Kato S, Tomson BN, Buys TP, Elkin SK, Carter JL, Kurzrock R


Understanding the genomic landscape of malignant mesothelioma may identify novel molecular drivers of this ultra-rare disease, which can lead to an expanded roster of targeted therapies and clinical trial options for patients with mesothelioma. We examined the molecular profiles of 42 patients with malignant mesothelioma (including pleural, peritoneal, and pericardial) that were referred by clinicians to be tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory using next-generation sequencing (NGS) (182 or 236 genes). Among 42 patients, there were 116 alterations, with 92 being distinct. The number of genomic alterations per patient ranged from 1 to 5 (median = 3). No two patients had identical molecular portfolios. The most common aberrations were in BAP1 (BRCA1-associated protein 1) (47.6% [20/42]), NF2 (38.1% [16/42]), and CDKN2A/B (loss) (35.7% [15/42]). BAP1 alterations and CDKN2A/B loss were associated with pleural mesothelioma (odds ratio [OR]: 3.4, p = 0.059 [BAP1] [trend]; OR: 5.8, p = 0.01 [CDKN2A/B]). All 42 patients had a molecular abnormality that was potentially actionable (median = 3 actionable alterations per patient, range, 1 to 5), and, in 40 patients (95.2%), a drug approved by the Food and Drug Administration (FDA) was applicable. In conclusion, each individual with malignant mesothelioma harbored a unique set of genomic aberrations, suggesting that NGS-based profiling of patients will be needed if patients are to be optimally matched to cognate treatments. All 42 patients had at least one alteration that was, in theory, pharmacologically tractable.