Loss of expression of BAP1 predicts longer survival in mesothelioma

Our plain-English summary of Loss of expression of BAP1 predicts longer survival in mesothelioma, by M. Farzin, C.W. Toon, A. Clarkson, et al (Pathology, 2015).

The study

• Authors: M. Farzin, C.W. Toon, A. Clarkson, L. Sioson, N. Watson, J. Andrici, A.J. Gill
• Journal: Pathology
• Published: 2015;47(4):302-7
• Cited by: 108 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

BRCA1-associated protein 1 (BAP1) is a tumour suppressor gene frequently inactivated in mesothelioma, rarely also in association with germline mutation. BAP1 mutations have been associated with improved prognosis and distinct clinicopathological features. We sought to determine the clinicopathological significance of BAP1 immunohistochemistry (IHC) in mesothelioma.We performed IHC on a tissue microarray (TMA) cohort comprising all available thoracic mesotheliomas encountered during the period 1991-2014 at our institution (n = 229). All cases were independently reviewed to confirm the diagnosis and subclassify as epithelioid, sarcomatoid or biphasic. The median age at diagnosis was 72 years; 188 (82.1%) were male; 120 (52.4%) were epithelioid (median survival 13.0 months), 67 (29.3%) sarcomatoid (median survival 5.6 months) and 42 (18.3%) biphasic (median survival 10.6 months). Negative staining for BAP1 (defined as completely absent nuclear staining in the presence of positive internal controls in non-neoplastic cells) occurred in 106 (46.3%) mesotheliomas. There was complete interobserver concordance for BAP1 IHC status. BAP1 loss was strongly associated with younger age at onset (p < 0.01) and epithelioid differentiation (p < 0.01). BAP1 loss predicted an improved median survival of 16.11 months (95% CI 12.16-20.06) versus 6.34 months (95% CI 5.34-7.34), p < 0.01. In a multivariate model including age, gender and histological type, BAP1 loss, younger age and epithelioid differentiation remained protective (all p < 0.01).If our results are confirmed by others, BAP1 IHC may have a role to predict prolonged survival or triage formal genetic testing for germline BAP1 mutation in patients presenting with mesothelioma.

In plain English

This study looked back at 229 patients with tissue-confirmed thoracic mesothelioma diagnosed at Royal North Shore Hospital, Sydney, Australia, from January 1991 to August 2014. The authors stained tumour samples for BAP1, the protein of a tumour suppressor gene, and recorded whether staining was completely lost. Asbestos exposure was not studied. In total, 106 tumours (46.3%) had lost BAP1. Loss was linked with younger age at diagnosis and epithelioid tumour type. Median survival was 16.11 months (95% CI 12.16 to 20.06) for patients whose tumours had lost BAP1, against 6.34 months (95% CI 5.34 to 7.34) for those with normal BAP1. After adjusting for age, gender and tumour type, BAP1 loss still went with a lower risk of death (hazard ratio 0.52; 95% CI 0.36 to 0.75). BAP1 loss was more common in women (56.1%) than men (44.1%), but this was not statistically significant across the whole cohort. The authors concluded that, if confirmed by others, BAP1 staining may help predict survival and decide who needs testing for inherited BAP1 mutation. They noted possible selection bias in the earliest years.

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 single-institution cohort study using immunohistochemistry (IHC) on a tissue microarray, with survival analysis (Kaplan–Meier and Cox regression)
• Who was studied: 229 patients with tissue-confirmed thoracic mesothelioma diagnosed January 1991 to August 2014 at the Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia. Cytology-only diagnoses and non-thoracic (abdominal) mesotheliomas were excluded, as were 15 thoracic cases with insufficient tissue. 188 (82.1%) were male, and ages at diagnosis ranged from 35 to 93 years.
• Exposure: Not asbestos. The factor studied was BAP1 protein staining in tumour cells, scored as negative (completely absent nuclear staining in all tumour cells with a positive internal control) or positive. The article gives no asbestos exposure data.
• Main results:
  • 106 of 229 mesotheliomas (46.3%) showed loss of BAP1 staining. The two observers agreed completely on the final result (kappa score of 1).
  • Loss of BAP1 was significantly associated with younger age at diagnosis (median 70 years versus 75 years for normal BAP1) and with epithelioid differentiation (62.5% of epithelioid, 17.9% of sarcomatoid and 45.2% of biphasic tumours had lost BAP1). Both p less than 0.01.
  • Median survival was 16.11 months (95% CI 12.16 to 20.06) for patients whose tumours had lost BAP1, versus 6.34 months (95% CI 5.34 to 7.34) for those with normal BAP1 expression (p less than 0.01).
  • In the unadjusted (univariate) analysis, BAP1 loss had a hazard ratio of death of 0.39 (95% CI 0.28 to 0.55). After adjusting for age, gender and histological subtype, the hazard ratio was 0.52 (95% CI 0.36 to 0.75; p less than 0.01). Histological subtype and age also remained significant, but gender did not (p = 0.87).
  • Across the whole cohort, BAP1 loss was more common in females (56.1%) than males (44.1%), but this was not statistically significant. When cases diagnosed before 1998 were excluded (186 cases), the association between female gender and BAP1 loss was statistically significant (p = 0.02).
  • Median overall survival for the whole cohort was 9.00 months (95% CI 7.21 to 10.80). By tumour type, median survival was 13.01 months for epithelioid, 10.60 months for biphasic and 5.59 months for sarcomatoid mesothelioma.
• The authors' conclusion: The authors concluded that loss of BAP1 staining identifies a distinct subgroup of mesotheliomas with younger age at onset, mainly epithelioid morphology and a significantly better prognosis. If others confirm the findings, BAP1 IHC could be part of routine work-up, mainly to predict outcome and possibly to triage genetic testing for germline BAP1 mutation.
• Limitations the authors state:
  • Possible selection bias against females with BAP1-negative epithelioid mesothelioma in the earliest years, when some cases may have been misdiagnosed as adenocarcinoma and not all adenocarcinomas could be reviewed.
  • Performing IHC on tissue microarray sections may be prone to sampling error.
  • The study was not designed to check IHC results against molecular (genetic) testing of BAP1.
  • BAP1 staining was not investigated in atypical but benign mesothelial proliferations, so its possible diagnostic use remains unproven.

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, Mesothelioma, Germline Mutation, Prognosis, Immunohistochemistry, Epithelioid, Sarcomatoid, Biphasic Mesothelioma.

Related studies

• 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)
• 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)
• The epithelioid BAP1-negative and p16-positive phenotype predicts prolonged survival in pleural mesothelioma — A. Chou, C.W. Toon, et al. (2018)
• Loss of BAP1 Expression in Atypical Mesothelial Proliferations Helps to Predict Malignant Mesothelioma — R. Pillappa, J.J. Maleszewski, et al. (2018)
• Loss of expression of BAP1 is very rare in non-small cell lung carcinoma — J. Andrici, T.R. Parkhill, et al. (2016)
• Loss of BRCA1-associated protein 1 (BAP1) expression is rare in non-small cell lung cancer — D. Owen, B.S. Sheffield, et al. (2017)

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