DNA methylation of GITR, OX40, 4-1BB, CD27, and CD40 correlates with BAP1 aberrancy and prognosis in uveal melanoma

Abstract

Uveal melanoma represents an aggressive tumor that responds mostly poorly to established melanoma treatments. Comprehensive methylation profiling of the next-generation immunotherapeutic target genes, for example, members of the tumor necrosis factor receptor superfamily, might allow for the development of companion predictive biomarkers. We have analyzed CpG sites within the immune checkpoint genes GITR, OX40, 4-1BB, CD27, and CD40 probed by the Illumina Infinium HumanMethylation450 BeadChip in N = 80 uveal melanomas included in The Cancer Genome Atlas with regard to BAP1 aberrancy, mRNA expression, and overall survival. In all analyzed immune checkpoint genes, BAP1 aberrancy was associated with decreased CpG methylation levels. We identified specific CpG sites that significantly correlated with BAP1 aberrancy, mRNA expression levels, and overall survival. Our results suggest epigenetic regulation of the analyzed immune checkpoint genes via DNA methylation in uveal melanoma and provide rationale for methylation testing in biomarker programs in clinical trials.

GZ17-6.02 kills PDX isolates of uveal melanoma

“…We found that GZ17-6.02 as a single agent increased BAP1 expression in uveal melanoma cells that was not altered by ERBB receptor inhibitors. In addition to histone ubiquitination, BAP1 also plays a role in regulating CpG site DNA methylation and histone methylation [21,[34][35][36][37][38]. The BAP1 promoter itself is subject to epigenetic regulation and hypermethylation of its DNA is inversely correlated with BAP1 mRNA expression.…”

“…In approximately 50% of UM patients, BRCA1 associated protein-1, BAP1, (ubiquitin carboxy-terminal hydrolase), a deubiquitinating enzyme, is mutated inactive, i.e., BAP1 is a tumor suppressor, and its loss of function subsequently was also associated with BAP1 acting as a suppressor of metastatic spread [17][18][19][20]. BAP1 is proposed to regulate the amount of ubiquitination of histones, regulating homeobox genes and long-term cell fate and stem-cell like behavior [21,22]. GZ17-6.02 simultaneously regulates multiple cell signaling processes which converge to kill tumor cells.…”