Liu-Smith Feng, Lu Yunxia
Department of Epidemiology, University of California Irvine, Irvine, CA 92697, USA.
Department of Medicine, University of California Irvine, Irvine, CA 92697, USA.
J Clin Med. 2020 Feb 3;9(2):411. doi: 10.3390/jcm9020411.
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.
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).
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.
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.
乳腺癌1号基因关联蛋白1（BAP1）种系突变使个体易患多种癌症，包括葡萄膜黑色素瘤（UM）和皮肤黑色素瘤（CM）。BAP1缺失在UM中很常见，且与较差的预后相关。BAP1缺失在CM中很少见，其预后尚不清楚。
从癌症基因组图谱（TCGA）数据库中检索UM和CM数据。采用Cox回归模型来检验BAP1 mRNA水平或拷贝数变异是否与总生存期（OS）相关。
BAP1低mRNA水平预示UM患者OS较差（风险比[HR]=9.57，95%置信区间[CI]：2.82，32.5），但在CM中却预示着较好的OS（HR=0.73，95%CI：0.56，0.95）。在对UM和CM的性别、年龄和分期进行校正后，或对CM的溃疡或Breslow深度进行校正后，这些结果保持不变。此外，低BAP1 mRNA水平预示50岁以上CM患者的OS较好，但对年轻患者则不然。共表达和富集分析揭示了与UM和CM肿瘤中BAP1表达水平相关的差异基因和突变。
与UM形成鲜明对比的是，低BAP1 mRNA水平与CM患者较好的OS显著相关。CM中高BAP1表达在蛋白水平上与细胞周期蛋白依赖性激酶1（CDK1）、B细胞淋巴瘤2（BCL2）和干细胞生长因子受体（KIT）的过表达显著相关，这可能解释了该亚组患者较差的OS。尽管有一小部分共享的共表达基因，但BAP1在CM和UM中的功能有很大差异。
