Large-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesothelioma

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dc.contributor.authorDe Rienzo, Assuntaen
dc.contributor.authorChirieac, Lucian R.en
dc.contributor.authorHung, Yin P.en
dc.contributor.authorSeverson, David T.en
dc.contributor.authorFreyaldenhoven, Samuelen
dc.contributor.authorGustafson, Corinne E.en
dc.contributor.authorDao, Nhien T.en
dc.contributor.authorMeyerovitz, Claire, Ven
dc.contributor.authorOster, Michela E.en
dc.contributor.authorJensen, Roderick V.en
dc.contributor.authorYeap, Beow Y.en
dc.contributor.authorBueno, Raphaelen
dc.contributor.authorRichards, William G.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2020-12-07T14:12:49Zen
dc.date.available2020-12-07T14:12:49Zen
dc.date.issued2020-09-17en
dc.description.abstractBRCA1-associated protein-1(BAP1) expression is commonly lost in several tumors including malignant pleural mesothelioma (MPM). Presence or absence of immunohistochemical BAP1 nuclear staining in tumor cells is currently used for differential diagnosis of MPM. In this study, a large cohort of 596 MPM tumors with available clinical data was analyzed to examine associations of BAP1 staining pattern with clinical and molecular features that may reflect the impact ofBAP1mutation on MPM biology. Cases were classified according to the BAP1 staining pattern of tumor cells. Exome and RNA-sequencing data were available for subsets of cases. Levels of mRNA encoding claudin 15 (CLDN15) and vimentin (VIM) were determined using RT-qPCR on 483 cases to estimate the relative proportions of epithelial-like and mesenchymal-like components in each tumor. Four BAP1 staining patterns were observed: single-pattern nuclear staining (36%), single-pattern cytoplasmic staining (25%), single-pattern absent staining (12%), and combinations of these staining patterns (27%). This study confirmed prior reports that nuclear BAP1 is more frequently associated with wild-typeBAP1and sarcomatoid histology. However, no associations between BAP1 staining pattern(s) and mutations in specific protein domains and/or mutation type were observed. BAP1 staining patterns were significantly associated (p < 0.001) withBAP1gene expression, MPM histologic subtypes, molecular clusters, and markers of epithelial-to-mesenchymal transition. Frequent observation of combinations of BAP1 staining patterns in MPM tumors indicated intra-tumoral heterogeneity ofBAP1status. Cytoplasmic BAP1 staining was identified as a putative indicator of favorable prognosis in non-epithelioid MPM. In conclusion, novel significant associations among different BAP1 staining patterns and subgroups of MPM tumors were observed, suggesting that the role ofBAP1in tumor progression may be more complex than its presumed tumor suppressor function. Cytoplasmic staining was identified as a putative indicator of favorable prognosis in non-epithelioid MPM, potentially addressing a critical need in clinical decision-making in this disease. (c) 2020 The Authors.The Journal of Pathologypublished by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.en
dc.description.notesThis work was supported by grants to RB from the National Cancer Institute (NCI 2 R01 CA120528-11A1) and the International Mesothelioma Program at Brigham and Women's Hospital. The study sponsors played no role in the study design, collection, analysis, interpretation of data, writing of the report, or decision to submit the paper for publication. We thank the Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Specialized Histopathology Core, which provided histology and immunohistochemistry service. Dana-Farber/Harvard Cancer Center is supported in part by an NCI Cancer Center Support Grant #NIH 5 P30 CA06516.en
dc.description.sponsorshipNational Cancer InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [NCI 2 R01 CA120528-11A1]; International Mesothelioma Program at Brigham and Women's Hospital; NCI Cancer Center Support GrantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [NIH 5 P30 CA06516]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1002/path.5551en
dc.identifier.eissn1096-9896en
dc.identifier.issn0022-3417en
dc.identifier.pmid32944962en
dc.identifier.urihttp://hdl.handle.net/10919/101027en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmesotheliomaen
dc.subjectBAP1en
dc.subjectimmunohistochemistryen
dc.subjecttumor suppressor geneen
dc.subjectintra-tumor heterogeneityen
dc.subjectepithelial-to-mesenchymal transitionen
dc.subjectgene expressionen
dc.subjectprognostic biomarkeren
dc.titleLarge-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesotheliomaen
dc.title.serialJournal of Pathologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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