Abstract
Background: BRCA1-Associated Protein 1 (BAP1) germline mutations predispose individuals to cancers, including uveal melanoma (UM) and cutaneous melanoma (CM). BAP1 loss is common in UM and is associated with a worse prognosis. BAP1 loss is rare in CM and the outcome is unclear. Methods: UM and CM data was retrieved from The Cancer Genome Atlas (TCGA) database. Cox regression model was performed to examine whether BAP1 mRNA levels or copy number variations were associated with overall survival (OS). Results: BAP1-low mRNA predicted a poor OS in UM (HR = 9.57, 95% CI: 2.82, 32.5) but a contrasting better OS in CM (HR = 0.73, 95% CI: 0.56, 0.95). These results remained unchanged after adjusting for sex, age, and stage in UM and CM, or after adjusting for ulceration or Breslow depth in CM. Additionally, low BAP1 mRNA predicted a better OS in CM patients older than 50 years but not in younger patients. Co-expression and enrichment analysis revealed differential genes and mutations that were correlated with BAP1 expression levels in UM and CM tumors. Conclusions: Low BAP1 mRNA was significantly associated with a better OS in CM patients, in sharp contrast to UM. High BAP1 expression in CM was significantly associated with over-expressed CDK1, BCL2, and KIT at the protein level which may explain the poor OS in this sub-group of patients. Function of BAP1 was largely different in CM and UM despite of a small subset of shared co-expressed genes.
Highlights
Germline mutations in BAP1 (BRCA1-Associated Protein 1) are associated with multiple types of hereditary cancers [1], which is classified as BAP1-TPDS (BAP1 Tumor Predisposition Syndrome) [2]
Tumor characteristics of the BAP1-TPDS-associated cutaneous melanoma (CM) are quite unique, exhibiting distinct morphology and histology which are similar to Atypical Spitz Tumors [2], which are substantially different from other common CM sub-types
High BAP1 mRNA expression levels were reported to be associated with a better survival in a cohort of primary CM patients [17], which was consistent with BAP1 function as a tumor suppressor in CM, but the authors stated that BAP1 level was perhaps confounded by other prognosis factors such as ulceration and Breslow depth in that study [17]
Summary
Germline mutations in BAP1 (BRCA1-Associated Protein 1) are associated with multiple types of hereditary cancers [1], which is classified as BAP1-TPDS (BAP1 Tumor Predisposition Syndrome) [2]. A meta-analysis of various cancer types with BAP1 mutations indicated that BAP1 mutations were associated with worse outcomes in renal cell carcinoma but not in other cancers [19]. High BAP1 mRNA expression levels were reported to be associated with a better survival in a cohort of primary CM patients [17], which was consistent with BAP1 function as a tumor suppressor in CM, but the authors stated that BAP1 level was perhaps confounded by other prognosis factors such as ulceration and Breslow depth in that study [17]
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