Molecular Characterization of Mesothelioma: Impact of Histologic Type and Site of Origin on Molecular Landscape

CDKN2A BAP1型 间皮瘤 荧光原位杂交 CDKN2B公司 病理 癌症研究 组织学 原位杂交 免疫组织化学 恶性肿瘤 医学 生物 基因 内科学 基因表达 癌症 遗传学 染色体
作者
Ibiayi Dagogo‐Jack,Russell W. Madison,Jochen K. Lennerz,Kuei‐Ting Chen,Julia F. Hopkins,Alexa B. Schrock,Lauren L. Ritterhouse,Ashley Lester,Keith A. Wharton,Mari Mino‐Kenudson,Natalie Danziger,Yin P. Hung,Douglas A. Mata,Jeffrey S. Ross
出处
期刊:JCO precision oncology [American Society of Clinical Oncology]
卷期号: (6) 被引量:19
标识
DOI:10.1200/po.21.00422
摘要

Mesothelioma is an aggressive malignancy with heterogeneous outcomes that are partly driven by the differential efficacy of existing therapies across histologic types and sites of origin. Large-scale molecular analysis of mesothelioma and its subtypes has the potential to inform future therapeutic strategies.We analyzed 1,294 mesotheliomas {980 pleural (malignant pleural mesothelioma [MPM]) and 314 peritoneal (malignant peritoneal mesothelioma [MPeM])} using next-generation sequencing, determined programmed death ligand-1 (PD-L1) expression and histology in a subset of cases, and assessed MTAP/CDKN2A copy-number status by fluorescence in situ hybridization and T-cell infiltration in an independent cohort.The molecular landscape of MPM was characterized by inactivating alterations in CDKN2A (49%), BAP1 (44%), CDKN2B (42%), MTAP (34%), and NF2 (33%). Compared with epithelioid MPM, nonepithelioid (ie, biphasic and sarcomatoid) MPM had identical tumor mutational burden (median 1.25 mut/Mb, P = .63), more commonly expressed PD-L1 (74% v 51%, P = .02), and was more likely to harbor MTAP, CDKN2A, and CDKN2B copy loss (P < .05). Fluorescence in situ hybridization confirmed that homozygous MTAP loss was enriched in nonepithelioid MPM. Relative to MPM, MPeM had comparable tumor mutational burden and PD-L1 expression. The molecular profile of MPeM was similar to MPM, with the distinction that PBRM1 alterations occurred at higher frequency (16% v 7%, P < .01). ALK rearrangements were only observed in MPeM.Regardless of histology and location, the molecular landscape of mesothelioma primarily consists of inactivating alterations in tumor suppressor genes, with enrichment of certain alterations in distinct subsets (eg, MTAP loss in nonepithelioid tumors). Given the limited efficacy of current therapies for this disease, novel approaches targeting recurring alterations should be explored.
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