Correlation between BAP1 Localization, Driver Mutations, and Patient Survival in Uveal Melanoma

SIMPLE SUMMARY: 100 uveal melanomas from the UK were analyzed for molecular biomarkers, including alterations of chromosomes 3 and 8, cellular localization of BAP1, and genes known to be mutated in uveal melanoma. Consistent with earlier studies, loss of nuclear BAP1 (nBAP1) predicted shorter overall survival. Tumors with BAP1 loss of function mutations frequently exhibited heterogeneous BAP1 staining, and tumors with ≥25% loss of nBAP1 were a more reliable prognosistic indicator than chromosome 3 loss (LOH3) or chromosome 8q gain. Regardless of mutation class, most BAP1 mutations led to loss of nBAP1 and aberrant expression of cBAP1. ABSTRACT: Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11). Immunohistochemical staining of BAP1 and interphase FISH for chromosomes 3 and 8 was performed, and cellular localization of BAP1 was correlated with BAP1 mutations. Wildtype (WT) BAP1 staining was characterized by nBAP1 expression with <10% cytoplasmic BAP1 (cBAP1). Tumors exhibited heterogeneity with respect to BAP1 staining with different percentages of nBAP1 loss: ≥25% loss of nuclear BAP1 (nBAP1) was superior to chr8q and LOH3 as a prognostic indicator. Of the successfully sequenced UMs, 38% harbored oncogenic mutations in GNA11 and 48% harbored mutations in GNAQ at residues 209 or 183. Of the secondary drivers, 39% of mutations were in BAP1, 11% were in EIF1AX, and 20% were in the SF3B1 R625 hotspot. Most tumors with SF3B1 or EIF1AX mutations retained nuclear BAP1 (nBAP1). The majority of tumor samples with likely pathogenic BAP1 mutations, regardless of mutation class, displayed ≥25% loss of nBAP1. This included all tumors with truncating mutations and 80% of tumors with missense mutations. In addition, 60% of tumors with truncating mutations and 82% of tumors with missense mutations expressed >10% cBAP1.