Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Hmeljak, Julija; Sanchez‐Vega, Francisco; Hoadley, Katherine A.; Shih, Juliann; Stewart, Chip; Heiman, David I.; Tarpey, Patrick; Danilova, Ludmila; Drill, Esther; Gibb, Ewan A.; Bowlby, Reanne; Kanchi, Rupa S.; Osmanbeyoglu, Hatice U.; Sekido, Yoshitaka; Takeshita, Jumpei; Newton, Yulia; Graim, Kiley; Gupta, Manaswi; Li, Diao; Gibbs, David L.; Thórsson, Vésteinn; Iype, Lisa; Kantheti, Havish S.; Severson, David T.; Ravegnini, Gloria; Desmeules, Patrice; Jungbluth, Achim A.; Travis, William D.; Đačić, Sanja; Chirieac, Lucian R.; Galateau-Salle, Françoise; Fujimoto, Junya; Husain, Aliya N.; Silveira, Henrique C. S.; Rusch, Valerie W.; Rintoul, Robert C.; Pass, Harvey I.; Kindler, Hedy L.; Zauderer, Marjorie G.; Kwiatkowski, David J.; Bueno, Raphael; Tsao, Anne S.; Creaney, Jenette; Lichtenberg, Tara M.; Leraas, Kristen; Bowen, Jay; Felau, Ina; Zenklusen, Jean C.; Akbani, Rehan; Cherniack, Andrew D.; Byers, Lauren A.; Noble, Michael S.; Fletcher, Jonathan A.; Robertson, Gordon; Shen, Ronglai; Aburatani, Hiroyuki; Robinson, Bruce; Campbell, Peter J.; Ladanyi, Marc

doi:10.1158/2159-8290.cd-18-0804

Cited by 482 publications

(802 citation statements)

References 60 publications

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“…2A-B), whereas, peritoneal mesothelioma has strong enrichment of C>T transition substitution mutation (Supplementary Figure 4). This mutational pattern in WDPM is different from those reported in pleural 4,5 or peritoneal 6 mesotheliomas.…”

Section: Wdpm Is Genetically Distinct From Malignant Mesotheliomacontrasting

confidence: 86%

“…To account for the low tumor cellularity in the WDPM samples and the absence of the matched control samples, we used strict mutation calls filtering criteria. Mutations were retained if (a) allele frequency 5 (AF) < 50%, (b) read quality pass > 50%, (c) average heterozygosity < 0.1, (d) mutation calls present in dbSNP database. We filtered out all In-Dels from our variant calls.…”

Section: Single Nucleotide Variant Callingmentioning

confidence: 99%

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Well-Differentiated Papillary Mesothelioma of the Peritoneum is Genetically Distinct from Malignant Mesothelioma

Shrestha

Nabavi

Volik

et al. 2019

Preprint

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Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process, and if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPM of the peritoneum, we have identified distinct mutations in EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C>A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked alterations involving BAP1, SETD2, NF2, CDKN2A/B, LASTS1/2, PBRM1 and SMARCC1 that are frequently altered in malignant mesotheliomas. We conclude that WDPMs are genetically distinct from malignant mesotheliomas, and based on observed mutations do not appear to be precursors of malignant mesotheliomas.

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Section: Wdpm Is Genetically Distinct From Malignant Mesotheliomacontrasting

confidence: 86%

Section: Single Nucleotide Variant Callingmentioning

confidence: 99%

Well-Differentiated Papillary Mesothelioma of the Peritoneum is Genetically Distinct from Malignant Mesothelioma

Shrestha

Nabavi

Volik

et al. 2019

Preprint

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“…For example, healthy spleen tissue showed a normal distribution of red and white pulp (CD3, CD20, CD68), presence of granulocytes (CD15), localization of indoleamine 2,3-dioxygenase 1 (IDO-1) in red pulp macrophages, and prominent PD-L1 expression in splenic sinusoids (CD31). Notably, we detected an unexpected strong and ubiquitous expression of the T cell checkpoint marker V domain Ig suppressor of T cell activation (VISTA) in mesothelioma, which is confirmed as a feature of mesothelioma in a recently described integrative genomic characterization study (Hmeljak et al, 2018).…”

Section: Ffpe-optimized Codex Enables Highly Multiplexed Fluorescencesupporting

confidence: 73%

Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front

Schürch

Bhate

Barlow

et al. 2019

Preprint

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Antitumoral immunity requires organized, spatially nuanced interactions between components of the immune tumor microenvironment (iTME). Understanding this coordinated behavior in effective versus ineffective tumor control will advance immunotherapies. We optimized CO-Detection by indEXing (CODEX) for paraffin-embedded tissue microarrays, enabling profiling of 140 tissue regions from 35 advanced-stage colorectal cancer (CRC) patients with 56 protein markers simultaneously. We identified nine conserved, distinct cellular neighborhoods (CNs)-a collection of components characteristic of the CRC iTME. Enrichment of PD-1 + CD4 + T cells only within a granulocyte CN positively correlated with survival in a high-risk patient subset. Coupling of tumor and immune CNs, fragmentation of T cell and macrophage CNs, and disruption of inter-CN communication was associated with inferioroutcomes. This study provides a framework for interrogating complex biological processes, such as antitumoral immunity, demonstrating an example of how tumors can disrupt immune functionality through interference in the concerted action of cells and spatial domains.

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“…The genomic landscape of MM shows frequent inactivation of the CDKN2AB locus that encodes for the p16 INK4A , p15 INK4B , and p14 ARF cell cycle inhibitor proteins and the Neurofibromatosis Type 2 ( NF2 ) tumor suppressor gene (Cheng et al, 1994; Sekido et al, 1995). BAP1 , encoding a nuclear deubiquitinase, was found to be mutated or deleted in multiple cancers, including ∼60% of human MM (Bott et al, 2011; Bueno et al, 2016; Carbone et al, 2012; Harbour et al, 2010; Hmeljak et al, 2018; Nasu et al, 2015; Testa et al, 2011). Furthermore, alterations in the Hippo pathway, mTOR, and chromatin modifiers were found in MM (Bueno et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice

Badhai

Pandey

Song

et al. 2020

Journal of Experimental Medicine

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We have generated mouse models of malignant mesothelioma (MM) based upon disruption of the Bap1, Nf2, and Cdkn2ab tumor suppressor loci in various combinations as also frequently observed in human MM. Inactivation of all three loci in the mesothelial lining of the thoracic cavity leads to a highly aggressive MM that recapitulates the histological features and gene expression profile observed in human patients. The tumors also show a similar inflammatory phenotype. Bap1 deletion alone does not cause MM but dramatically accelerates MM development when combined with Nf2 and Cdkn2ab (hereafter BNC) disruption. The accelerated tumor development is accompanied by increased Polycomb repression and EZH2-mediated redistribution of H3K27me3 toward promoter sites with concomitant activation of PI3K and MAPK pathways. Treatment of BNC tumor–bearing mice with cisplatin and pemetrexed, the current frontline treatment, prolongs survival. This makes the autochthonous mouse model described here very well suited to explore the pathogenesis of MM and validate new treatment regimens for MM, including immunotherapy.

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Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Cited by 482 publications

References 60 publications

Well-Differentiated Papillary Mesothelioma of the Peritoneum is Genetically Distinct from Malignant Mesothelioma

Well-Differentiated Papillary Mesothelioma of the Peritoneum is Genetically Distinct from Malignant Mesothelioma

Coordinated cellular neighborhoods orchestrate antitumoral immunity at the colorectal cancer invasive front

Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice

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