Hoffmann Friederike, Fröhlich Anne, Sirokay Judith, de Vos Luka, Zarbl Romina, Dietrich Jörn, Strieth Sebastian, Landsberg Jennifer, Dietrich Dimo
Department of Dermatology and Allergology.
Department of Otorhinolaryngology, University Medical Center Bonn (UKB), Bonn, Germany.
Melanoma Res. 2023 Apr 1;33(2):116-125. doi: 10.1097/CMR.0000000000000879. Epub 2023 Feb 1.
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, CD 27, 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.
葡萄膜黑色素瘤是一种侵袭性肿瘤，对现有的黑色素瘤治疗方法大多反应不佳。对下一代免疫治疗靶基因进行全面的甲基化分析，例如肿瘤坏死因子受体超家族的成员，可能有助于开发伴随预测生物标志物。我们使用Illumina Infinium HumanMethylation450 BeadChip对癌症基因组图谱中纳入的N = 80例葡萄膜黑色素瘤的免疫检查点基因GITR、OX40、4-1BB、CD27和CD40内的CpG位点进行了分析，涉及BAP1异常、mRNA表达和总生存期。在所有分析的免疫检查点基因中，BAP1异常与CpG甲基化水平降低相关。我们鉴定出了与BAP1异常、mRNA表达水平和总生存期显著相关的特定CpG位点。我们的结果表明，葡萄膜黑色素瘤中通过DNA甲基化对所分析的免疫检查点基因进行表观遗传调控，并为临床试验中生物标志物计划的甲基化检测提供了理论依据。
