Association of BAP1 expression with clinicopathologic features, Ki-67 proliferative activity, and clinical outcomes in epithelioid mesothelioma: a multicenter retrospective study

BRCA1-associated protein 1 (BAP1) loss is common in mesothelioma, but its relationship with proliferation and outcome remains incompletely defined. We evaluated associations of BAP1 expression with primary site, clinicopathologic features, Ki-67, and progression-related outcomes in epithelioid mesothelioma and explored combined BAP1/Ki-67 risk stratification. We retrospectively analyzed a multicenter mesothelioma database including 50 patients with epithelioid mesothelioma and interpretable BAP1 immunohistochemistry (26 pleural and 24 peritoneal tumors). Tumors were classified as complete nuclear BAP1 loss or retained expression. Ki-67 was standardized as the percentage of positive tumor cells. Fisher’s exact test, Mann-Whitney U test, Welch’s t test, and Kaplan-Meier/log-rank analyses were used as appropriate. An exploratory combined BAP1/Ki-67 model was evaluated. Complete BAP1 loss was identified in 17 of 50 patients (34.0%). BAP1 status was associated with primary site ( P = 0.003), with loss enriched in pleural tumors. Among 36 patients with evaluable Ki-67, median Ki-67 was 10.0% with BAP1 loss and 15.0% with retained expression ( P = 0.150). In pleural epithelioid mesothelioma, median Ki-67 was lower with BAP1 loss (10.0% vs. 50.0%, P = 0.047); means were 14.36% and 39.44% ( P = 0.028). BAP1 loss showed a trend toward longer progression-free survival in pleural tumors (HR = 0.36, 95% CI 0.12–1.09; P = 0.071). With a 10% Ki-67 cutoff, progression risk was lower in the retained/low group (HR = 0.339, 95% CI 0.116–0.992; P = 0.048) and loss/low group (HR = 0.202, 95% CI 0.056–0.727; P = 0.014) than in the retained/high reference group. Complete BAP1 deletion is more prevalent in pleural epithelioid mesothelioma and is associated with lower proliferative activity. Although BAP1 deletion shows a trend towards prolonged progression time, the available data are insufficient to establish its independent prognostic value. Exploratory subgroup analyses revealed differences in estimated progression-free survival (PFS) across different BAP1/Ki-67 subgroups; however, owing to the small sample size and the observation of more favourable estimates in both low Ki-67 groups, it is not yet possible to draw conclusions regarding the incremental prognostic value of BAP1 beyond that of Ki-67. These findings should be regarded as exploratory subgroup associations in this study and require further validation in larger cohorts with centre-reviewed data and complete time-to-event data.