Comprehensive genomic profiling of malignant peritoneal mesothelioma (MPeM) reveals key genomic alterations (GAs) distinct from malignant pleural mesothelioma (MPM).
Authors: Lynne O. Chapman, Michael J. Overman, Anneleis Willett, Mark Knafl, Szu-Chin Fu, Anais Malpica, Christopher Scally, Paul F. Mansfield, Aurelio Aurelio Matamoros, Ajaykumar Morani, Scott Eric Woodman, Boris Sepesi, Reza J. Mehran, Cara L. Haymaker, Gauri Rajani Varadhachary, Anne S. Tsao, Keith Fournier, Kanwal Pratap Singh Raghav
Journal: Journal of Clinical Oncology (2021)

8557 Background: MPeM is a rare and aggressive cancer with very limited treatment options. Lack of dedicated research has impeded improvements in outcomes. Defining prevalent GAs is a critical unmet need for use of targeted therapies in these patients. Although MPeM is notably distinct from MPM vis-à-vis epidemiologic and clinical attributes, the genomic underpinings of these differences have yet to be established. We aimed at describing a comprehensive genomic profile (CGP) of MPeM in comparison to MPM. Methods: We performed a retrospective comparative analysis between 89 patients with MPeM and 241 patients with MPM (N = 330) who underwent CGP using CLIA certified next-generation sequencing assays. The cohort was generated using mesothelioma patients at MD Anderson Cancer Center (N = 223) and supplemented by additional mesothelioma patients (N = 107) from a publicly available database from Memorial Sloan Kettering Cancer Center, the MSK-IMPACT database. Essential clinicopathological variables were collected. Descriptive statistics, Fisher’s exact and Mann-Whitney tests were used for comparison. Kaplan-meier method and log rank tests were used for overall survival (OS) estimates. Results: MPeM cohort (vs. MPM) had more women (54% vs. 31%, P &lt; 0.001) and younger age at diagnosis (56 vs. 69 years, P &lt; 0.001). Histology was epithelioid, biphasic and sarcomatoid in 86%, 7% and 7% cases, a distribution similar to MPM cohort. At least 1 GA was found in 64 (72% vs. 82% in MPM, P = 0.044) of MPeM patients with a median of 1 (range 1 – 12) (vs. a median of 2, range 1 – 24, P &lt; 0.001) GA per patient. A significantly lower proportion of MPeM patients had ≥ 3 mutations (14% vs. 26%, OR 2.1, P = 0.028) per patient. The most frequent mutations were present in the following genes: TP53 (24%), BAP1 (16%), NF2 (15%), MET (9%) and TRAF7, KIT and PIK3CA (each 6%). MPeM patients harbored more mutations in MET (9% vs. &lt; 1%, P &lt; 0.001) and TRAF7 (6% vs. &lt; 1%, P = 0.02) but fewer mutations in BAP1 (16% vs. 32%, P = 0.003) and CDKN2B (0% vs. 5%, P = 0.041). The most common copy number variations (CNVs: amplifications or deletions) were seen in BAP1, MCL1, SETD2, WT1 (each 2%) and AURKA (1%) genes. Among genes with CNVs, MPeM had a lower rate of deletions in CDKN2A (1% vs. 6%, P = 0.040). Among more common GAs, only BAP1 mutations appeared to be associated with poor OS (45.7 vs. 127.1 months, HR 2.5, 95%CI: 0.6 – 10.1, P = 0.050) in patients with MPeM. Conclusions: In this large cohort with CGP, we identified potential molecular drivers in MPeM and demonstrated key genomic differences between MPeM and MPM. MPeM is frequently driven by GAs involved in cell cycle control, a potentially targetable pathway. Despite this insight from CGP, a large subset of patients do not have actionable GAs and for these patients, further collaborative trans-“omic” research efforts are needed to advance potential therapeutic options.