Different prognostic roles of tumor suppressor gene BAP1 in cancer: A systematic review with meta-analysis

Our plain-English summary of Different prognostic roles of tumor suppressor gene BAP1 in cancer: A systematic review with meta-analysis, by C. Luchini, N. Veronese, S. Yachida, et al (Genes, Chromosomes & Cancer, 2016).

The study

• Authors: C. Luchini, N. Veronese, S. Yachida, L. Cheng, A. Nottegar, B. Stubbs, M. Solmi, P. Capelli, A. Pea, M. Barbareschi, M. Fassan, L.D. Wood, A. Scarpa
• Journal: Genes, Chromosomes & Cancer
• Published: 2016;55(10):741-9
• Type of article: Meta-analysis, Systematic review
• Cited by: 55 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Biallelic inactivation of the tumor suppressor gene BRCA1-associated protein 1 (BAP1) has been demonstrated in several cancers, but its prognostic role has not been completely explained. We aimed to investigate the risk associated with loss of BAP1 (BAP1-) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS were searched from database inception until 09/15/2015 without language restrictions. Prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of BAP1 (BAP1+) vs. BAP1- were included. Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to BAP1- adjusted for potential confounders. From 261 hits, 12 studies (including 13 cohorts) with 3,447 participants (BAP1-: n = 697; BAP1+: n = 2,750), with a median follow-up over 60 months, were meta-analyzed. Compared to BAP1+, BAP1- significantly increased all-cause mortality, cancer-specific mortality and risk of recurrence in all the tumor types analyzed, except for mesothelioma, in which the presence of BAP1 mutations correlates with a better prognosis. Furthermore, we demonstrated that BAP1 mutated colorectal and renal carcinomas are associated with high-tumor grading (P < 0.0001), and that BAP1 mutated is more common in women than in men (P < 0.0001). In conclusion, on the basis of our meta-analysis, we have demonstrated a peculiar role of BAP1 in influencing the prognosis in cancer. Thus, BAP1 could be considered as an important potential target for personalized medicine. © 2016 Wiley Periodicals, Inc.

© 2016 Wiley Periodicals, Inc.

In plain English

This was a systematic review with meta-analysis. The authors searched two databases up to 15 September 2015 and pooled 12 studies (13 cohorts). They compared BAP1-negative tumors, as defined by each study's staining criteria or mutation testing, with BAP1-positive tumors. The studies covered 3,447 patients (697 BAP1-negative, 2,750 BAP1-positive). Cancers included mesothelioma (two studies), uveal melanoma and clear cell kidney cancer. The study did not examine asbestos exposure. Across 10 studies, BAP1 loss was linked to higher death from any cause (risk ratio 1.82, 95% CI 1.34 to 2.47). Separate pools linked it to higher cancer death (3 studies, 2.46, 1.96 to 3.09) and recurrence (4 studies, 2.37, 1.63 to 3.46). Pooled adjusted hazard ratios from 5 studies showed no statistically significant link with death from any cause (1.75, 0.83 to 3.71) until one mesothelioma study was removed. In the two mesothelioma studies, BAP1 loss went with lower death from any cause (risk ratio 0.92, 0.87 to 0.97). The authors concluded that BAP1 loss is associated with poor prognosis in all cancer types analyzed except mesothelioma. They noted the included studies were retrospective and results varied widely.

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: Systematic review with meta-analysis of observational cohort studies, searching PubMed and SCOPUS from database inception to 15 September 2015
• Who was studied: 12 studies (13 cohorts) with 3,447 cancer patients: 697 BAP1-negative and 2,750 BAP1-positive, with a median follow-up of 60 months. Six studies were from the USA, three from Europe, two from Asia and one from Australia. The cancers were uveal melanoma (4 studies), clear cell renal cell carcinoma (3), and mesothelioma (2: Zauderer 2013, on pleural mesothelioma, and Farzin 2015). There was one study each of cholangiocarcinoma, non-small cell lung cancer and colorectal cancer.
• Exposure: BAP1 status of the tumor. Eight studies assessed BAP1 by immunohistochemistry (nuclear staining), each using its own criteria for calling a tumor negative; for example, the lung cancer study by Fan et al. counted expression in fewer than 30% of cells as negative. Four studies assessed BAP1 mutations by DNA sequencing. BAP1-negative tumors were compared with BAP1-positive tumors. Asbestos exposure was not an exposure in this analysis.
• Main results:
  • Across 10 studies (479 BAP1-negative and 1,481 BAP1-positive patients), BAP1 loss was associated with higher all-cause mortality. The risk ratio was 1.82 (95% CI 1.34 to 2.47), p less than 0.0001, with high heterogeneity (I2 = 90%).
  • Across 3 studies (194 BAP1-negative and 1,400 BAP1-positive patients), cancer-specific mortality was higher in the BAP1-negative group. The risk ratio was 2.46 (95% CI 1.96 to 3.09).
  • Across 4 studies (284 BAP1-negative and 685 BAP1-positive patients), BAP1 loss was associated with a higher risk of recurrence. The risk ratio was 2.37 (95% CI 1.63 to 3.46).
  • Using adjusted hazard ratios from 5 studies (377 BAP1-negative and 794 BAP1-positive patients), BAP1 loss was not significantly associated with all-cause mortality. The hazard ratio was 1.75 (95% CI 0.83 to 3.71), p = 0.14.
  • When the mesothelioma study by Farzin et al. (2015) was removed from the adjusted analysis, the hazard ratio became significant: 2.13 (95% CI 1.42 to 3.09).
  • In mesothelioma, BAP1 loss was associated with lower all-cause mortality. The pooled risk ratio from 2 studies was 0.92 (95% CI 0.87 to 0.97), and the adjusted hazard ratio from 1 study was 0.52 (95% CI 0.36 to 0.75). The authors described this as protective.
  • BAP1-negative patients were more often women than BAP1-positive patients (40% vs. 29%, p less than 0.0001).
  • BAP1-negative patients more often had high-grade (G3-4) cancers than BAP1-positive patients (59% vs. 27%, p less than 0.0001).
  • The authors found evidence of publication bias for the unadjusted all-cause mortality estimate. After trim-and-fill correction, the risk ratio was 1.53 (95% CI 1.12 to 2.02).
• The authors' conclusion: The authors concluded that BAP1 mutation status is associated with a poor prognosis in all the cancer types analyzed except mesothelioma, where BAP1 mutation appears protective. They said further studies of mesothelioma are needed to clarify the prognostic role of BAP1.
• Limitations the authors state:
  • The included studies were retrospective.
  • Data on other illnesses, such as cardiovascular disease, were not consistently reported.
  • Heterogeneity between studies was high for almost all outcomes. The authors attributed this to the mesothelioma studies.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Suppressor Gene, BAP1, Systematic Review, Meta-Analysis, Hazard Ratio, Mesothelioma, Prognosis, Carcinoma.

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• The spectrum of tumors harboring BAP1 gene alterations — Y. Laitman, J. Newberg, et al. (2021)
• Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells — S. Hakiri, H. Osada, et al. (2015)
• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)
• Novel LRRK2 mutations and other rare, non-BAP1-related candidate tumor predisposition gene variants in high-risk cancer families with mesothelioma and other tumors — M. Cheung, Y. Kadariya, et al. (2021)

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