Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin–proteasome pathway as a therapeutic target in poor prognosis tumors

Cappellini, Gian Carlo Antonini; Kim, H K; Hesdorffer, Mary; Taub, Robert N.; Powell, Charles A.

doi:10.1038/sj.onc.1209809

Cited by 47 publications

(30 citation statements)

References 32 publications

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“…1 Last, differential RNA profiling and proteinexpression analysis suggest a contrasting molecular pathogenesis between these two entities. 40,41 Despite the differences between peritoneal and pleural mesotheliomas, previous studies have demonstrated homozygous CDKN2A deletions in malignant mesothelioma are a poor prognostic indicator regardless of site. 22,25,32 Consistent with these reports, we found that patients with peritoneal mesothelioma harboring a homozygous CDKN2A deletion had decreased PFS and OS.…”

Section: Discussionmentioning

confidence: 99%

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

et al. 2016

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Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n = 25, 29%), hemizygous NF2 loss (n = 30, 35%), and/or loss of BAP1 protein expression (n = 49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progressionfree survival (Po 0.02) and poor overall survival (Po 0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (Po 0.01) and overall survival rate of 18% with a median of 8 months (Po 0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.

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Section: Discussionmentioning

confidence: 99%

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

et al. 2016

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“…Microarray analysis of human biphasic versus epithelial mesothelioma of the peritoneum showed that the more aggressive biphasic type had overexpressed proteasome genes [68]. Bortezomib, a proteasome inhibitor approved for second-line treatment of multiple myeloma, had anti-tumour effect on mesothelioma cells in vitro [68] and in a tumour xenograft study on mice [69].…”

Section: Targeted Therapiesmentioning

confidence: 98%

Malignant pleural mesothelioma: Genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets

Røe¹,

Anderssen²,

Sandeck³

et al. 2010

Lung Cancer

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“…These studies have resulted in the discovery of a novel biomarker, osteopontin [106], and the proteasome as a novel treatment target [107,108], as well as a gene signature for prognostication [109], although it has not gained general acceptance yet [110].…”

Section: Figurementioning

confidence: 99%

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

2015

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Asbestos is the term for a family of naturally occurring minerals that have been used on a small scale since ancient times. Industrialisation demanded increased mining and refining in the 20th century, and in 1960, Wagner, Sleggs and Marchand from South Africa linked asbestos to mesothelioma, paving the way to the current knowledge of the aetiology, epidemiology and biology of malignant pleural mesothelioma. Pleural mesothelioma is one of the most lethal cancers, with increasing incidence worldwide. This review will give some snapshots of the history of pleural mesothelioma discovery, and the body of epidemiological and biological research, including some of the controversies and unresolved questions. Translational research is currently unravelling novel circulating biomarkers for earlier diagnosis and novel treatment targets. Current breakthrough discoveries of clinically promising noninvasive biomarkers, such as the 13-protein signature, microRNAs and the BAP1 mesothelioma/cancer syndrome, are highlighted. The asbestos history is a lesson to not be repeated, but here we also review recent in vivo and in vitro studies showing that manmade carbon nanofibres could pose a similar danger to human health. This should be taken seriously by regulatory bodies to ensure thorough testing of novel materials before release in the society. @ERSpublications Malignant pleural mesothelioma is a cancer with increasing death tolls due to the past and present use of asbestos http://ow.ly/DhA2y

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Molecular profiling of malignant peritoneal mesothelioma identifies the ubiquitin–proteasome pathway as a therapeutic target in poor prognosis tumors

Cited by 47 publications

References 32 publications

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

Malignant pleural mesothelioma: Genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets

Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic

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