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

Our plain-English summary of Large-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesothelioma, by A. De Rienzo, L.R. Chirieac, Y.P. Hung, et al (The Journal of Pathology, 2021).

The study

• Authors: A. De Rienzo, L.R. Chirieac, Y.P. Hung, D.T. Severson, S. Freyaldenhoven, C.E. Gustafson, N.T. Dao, C.V. Meyerovitz, M.E. Oster, R.V. Jensen, B.Y. Yeap, R. Bueno, W.G. Richards
• Journal: The Journal of Pathology
• Published: 2021;253(1):68-79
• Cited by: 31 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

BRCA1-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 of BAP1 mutation 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-type BAP1 and 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) with BAP1 gene 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 of BAP1 status. 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 of BAP1 in 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. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

In plain English

This study examined stored tumor samples from 596 patients with malignant pleural mesothelioma. The tumors were removed at surgery and collected at Brigham and Women's Hospital in Boston between 1989 and 2015. Pathologists stained the samples for the protein BAP1 and sorted them by where the stain appeared in tumor cells. Staining was only nuclear in 215 tumors (36%), only cytoplasmic in 147 (25%), absent in 73 (12%), and mixed in 161 (27%). The staining patterns were not associated with patients' self-reported asbestos exposure. Nuclear staining was linked to the absence of BAP1 gene mutations. It became more frequent moving from epithelioid toward sarcomatoid tumors. Among patients with non-epithelioid tumors, those with only cytoplasmic staining had longer median survival than those with other patterns (17.4 versus 9.3 months, hazard ratio 0.62). In epithelioid tumors no significant survival association was found. The authors concluded that cytoplasmic staining is a putative indicator of better prognosis in non-epithelioid disease, if validated. They noted that staining often varied within a single tissue section.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective laboratory study of archived surgical tumor samples, using immunohistochemistry (BAP1 staining) and, for subsets of cases, gene sequencing and gene expression data, with survival analysis
• Who was studied: 596 patients diagnosed with malignant pleural mesothelioma (MPM) whose tumors were surgically resected, with samples collected between 1989 and 2015 at Brigham and Women's Hospital, Boston. There were 439 males and 157 females, with a median age of 66 (range 18 to 86). Histology: 342 epithelioid, 187 biphasic, 67 sarcomatoid/desmoplastic. BAP1 sequencing data were available for 263 cases, RNA-sequencing for 174, and CLDN15/VIM testing for 483.
• Exposure: The study did not measure asbestos exposure. The factor studied was the BAP1 protein staining pattern in tumor cells (nuclear, cytoplasmic, absent, or combinations). Asbestos exposure was recorded only by self-report: Table 1 lists 302 (67%) yes, 152 (26%) no and 42 (7%) unknown.
• Main results:
  • Among all 596 tumors: single-pattern nuclear staining in 215 (36%), single-pattern cytoplasmic in 147 (25%), single-pattern absent in 73 (12%), and combinations of patterns in 161 (27%).
  • No associations with staining patterns were found when patients were grouped by self-reported asbestos exposure or by neoadjuvant chemotherapy before surgery.
  • Among the 263 cases with sequencing data, single-pattern nuclear staining was associated with absence of BAP1 single nucleotide and small variant (SNSV) mutations (p less than 0.001). Single-pattern absent staining was associated with these mutations (p = 0.006).
  • No association was found between staining pattern and mutations in specific protein domains (including UCH and NLS2) or mutation type (p = 0.21).
  • Single-pattern nuclear staining became more frequent across the histologic spectrum from epithelioid to sarcomatoid tumors (p less than 0.001 for trend).
  • At least one SNSV mutation was found in 62 of 146 (42%) epithelioid, 35 of 85 (41%) biphasic, and 4 of 32 (13%) sarcomatoid/desmoplastic samples.
  • Among patients with non-epithelioid tumors, single-pattern cytoplasmic staining was associated with longer survival than other staining patterns: median 17.4 versus 9.3 months, HR = 0.62, p = 0.005.
  • Among patients with biphasic tumors considered separately, single-pattern cytoplasmic staining was associated with longer survival than other patterns: median 21.6 versus 11.6 months, HR = 0.62, p = 0.009.
  • In epithelioid patients, no significant association between staining pattern and survival was found. Single-pattern absent staining showed a non-significant trend toward shorter survival (HR = 1.31 versus single-pattern nuclear; p = 0.167).
  • No difference in patient survival was observed between cases with wild-type versus mutated BAP1 (p = 0.58).
• The authors' conclusion: The authors concluded that BAP1 staining location is associated with clinical, histologic and molecular features, and that combinations of patterns are frequent. They concluded that single-pattern nuclear staining is associated with wild-type BAP1 and sarcomatoid subtype. They described single-pattern cytoplasmic staining as a putative indicator of favorable prognosis in non-epithelioid MPM, which, if validated, could help sort patients into risk groups.
• Limitations the authors state:
  • Staining often varied within a single tissue section. Undetected variation within tumors may have caused mismatch between the mutation analysis (done on frozen tissue) and the blocks used for staining.
  • Only mutation data from deep sequencing were considered, so not all relevant BAP1 genetic alterations may have been identified.
  • Epigenetic analyses of the BAP1 promoter were not performed, so epigenetic causes of lost nuclear staining cannot be ruled out.
  • Most sarcomatoid tumors showed single-pattern nuclear staining, so there was not enough statistical power to analyze sarcomatoid tumors separately.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Pleural Mesothelioma, Differential Diagnosis, Sarcomatoid, Histology, Histological Subtype, Prognosis, Non-epithelioid.

Related studies

• Malignant cells from pleural fluids in malignant mesothelioma patients reveal novel mutations — S. Sneddon, I. Dick, et al. (2018)
• Retrospective response analysis of BAP1 expression to predict the clinical activity of systemic cytotoxic chemotherapy in mesothelioma — N. Kumar, D. Alrifai, et al. (2019)
• CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma — M. Betti, A. Aspesi, et al. (2016)
• Loss of expression of BAP1 is a useful adjunct, which strongly supports the diagnosis of mesothelioma in effusion cytology — J. Andrici, A. Sheen, et al. (2015)
• Loss of BAP1 expression is very rare in peritoneal and gynecologic serous adenocarcinomas and can be useful in the differential diagnosis with abdominal mesothelioma — J. Andrici, J. Jung, et al. (2016)
• BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas — N. Leblay, F. Leprêtre, et al. (2017)

Browse more research in The Journal of Pathology, or return to medical research.