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ENGLISH ABSTRACT
BAP1、 FOXO3和 ITPR2基因表达变化与葡萄膜黑色素瘤转移和预后关联分析
李洋
冯宇
刘月明
魏文斌
作者及单位信息
·
DOI： 10.3760/cma.j.cn115989-20200714-00495
Relationship between BAP1, FOXO3 and ITPR2 gene expression and metastasis and prognosis of uveal melanoma
Li Yang
Feng Yu
Liu Yueming
Wei Wenbin
Authors Info & Affiliations
Li Yang
Beijing Tongren Hospital, Capital Medical University, Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing 100730, China
Feng Yu
Beijing Tongren Hospital, Capital Medical University, Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing 100730, China
Liu Yueming
Beijing Tongren Hospital, Capital Medical University, Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing 100730, China
Wei Wenbin
Beijing Tongren Hospital, Capital Medical University, Beijing Tongren Eye Center, Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing 100730, China
·
DOI： 10.3760/cma.j.cn115989-20200714-00495
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摘要

目的鉴定分子遗传学水平上与葡萄膜黑色素瘤(UM)转移和预后相关的潜在标志物。

方法收集肿瘤基因组图谱数据库中2007—2019年80例UM样本的信息，根据是否发生转移分为转移组18例和非转移组62例。采用R软件中的maftools函数包分析UM样本中的基因突变种类、变异类型、单核苷酸变异(SNV)类型和基因突变比例，计算肿瘤突变负荷；采用R软件中的edgeR软件包分析转移组和非转移组间的差异表达基因(DEGs)；采用KOBAS工具对DEGs的京都基因与基因组百科全书通路进行富集，筛选出预后相关基因。采用survival函数包建立Cox回归模型验证基因突变情况和DEGs的预后评价。

结果UM基因突变中以错义突变为主，主要变异类型为SNV，UM基因突变负荷低。与非转移组相比，转移组中存在562个DEGs，在基因集富集分析中，3条与眼部疾病和癌症相关的通路显著富集，分别为玻璃体视网膜变性、癌症相关蛋白多糖和PI3K-Akt信号通路。转移组 BAP1、 FOXO3和 ITPR2基因表达量分别为2 982.50(1 251.50，5 637.00)、1 223.00(914.75，2 706.25)和2 201.50(570.75，4 814.00)，与非转移组的5 225.00(2 281.25，8 784.00)、2 293.50(1 254.25，3 693.75)和474.00(153.00，1 437.75)比较，转移组 BAP1和 FOXO3表达量显著下调， ITPR2表达量显著上调，差异均有统计学意义( Z＝-1.786、-1.982、-3.065，均 P<0.10)。采用Cox模型单因素分析显示， BAP1基因突变、 FOXO3基因表达下调和 ITPR2基因表达上调与不良预后显著相关(均 P<0.10)。

结论 BAP1基因突变、 FOXO3基因下调和 ITPR2基因上调可作为UM转移和预后的潜在生物标志物。

葡萄膜黑色素瘤;转移;预后;生物标志物
ABSTRACT

ObjectiveTo explore the potential biomarkers for the metastasis and prognosis of uveal melanoma (UM) from molecular genetics.

MethodsThe data of 80 UM samples including 18 metastatic cases and 62 non-metastatic cases between 2007 and 2019 were downloaded from The Cancer Genome Atlas database.The tumor mutation burden and gene mutation information, including mutant genes, variant type, the proportion of single nucleotide variation (SNV) and mutation proportion, were analyzed using maftools package in R software, and the differentially expressed genes (DEGs) between the two groups were screened using edgeR package.The Kyoto Encyclopedia of Genes and Genomes enrichment analysis based on the DEGs was performed to screen prognosis-associated genes using KOBAS.Cox regression model was established using survival package in R software to verify the association between gene mutation and DEGs and the prognosis of UM patients.

ResultsThe mutation analysis showed that missense mutation accounted for a large proportion in the mutation of UM samples, and the main variant type was SNV, and the mutation burden of UM was low.Compared with the non-metastatic UM samples, 562 DEGs were identified in the metastatic UM samples.Three pathways, including vitreoretinal degeneration, proteoglycans in cancer, and PI3K-Akt pathway, were significantly enriched.The expression levels of BAP1, FOXO3 and ITPR2 were 2 982.50 (1 251.50, 5 637.00), 1 223.00 (914.75, 2 706.25) and 2 201.50 (570.75, 4 814.00)in the metastatic group, and 5 225.00 (2 281.25, 8 784.00), 2 293.50 (1 254.25, 3 693.75) and 474.00 (153.00, 1 437.75) in the non-metastatic group, respectively.The expression of BAP1 and FOXO3 among the DEGs were significantly down-regulated and ITPR2 expression was significantly up-regulated in the metastatic group in comparison with the non-metastatic group ( Z=-1.786, -1.982, -3.065; all at P<0.10). The survival analysis revealed BAP1 mutation, decreased FOXO3 expression and increased ITPR2 expression were associated with inferior survival of UM patients (all at P<0.10).

Conclusions BAP1 mutation, up-regulation of FOXO3 and down-regulation of ITPR2 might be potential biomarkers for the metastasis and prognosis of UM.

Uveal melanoma;Metastasis;Prognosis;Biomarkers
Wei Wenbin, Email: mocdef.3ab61rtnibnewiew
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引用本文

李洋,冯宇,刘月明,等. BAP1、 FOXO3和 ITPR2基因表达变化与葡萄膜黑色素瘤转移和预后关联分析 [J]. 中华实验眼科杂志,2021,39(08)：700-707.

DOI:10.3760/cma.j.cn115989-20200714-00495

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葡萄膜黑色素瘤(uveal melanoma，UM)是成年人眼内常见的原发性恶性肿瘤，其起源于葡萄膜中的黑色素细胞，约占全身黑色素瘤的5% [ 1 , 2 ]。UM多发于浅肤色白人，除种族因素外，UM的危险因素还包括脉络膜痣、眼(皮肤)黑色素细胞增多症 [ 3 , 4 , 5 , 6 ]。尽管紫外线辐射是皮肤黑色素瘤的重要危险因素，但其是否促使UM的发生仍存在争议 [ 7 ]。UM的常见远处转移部位为肝脏，近一半的UM患者最终发展为肝转移 [ 8 , 9 ]。当前，对于转移性UM尚缺少明确有效的治疗策略，发生转移后患者中位生存时间不足1年 [ 10 ]。既往研究发现，肿瘤大小、睫状体侵犯、眼外扩散等影像学表现和组织学上皮细胞型、有丝分裂核像、血管袢为预后不良的标志 [ 11 , 12 ]；染色体拷贝数变异水平上3号染色体短臂丢失以及8号染色体长臂扩增者的预后较差 [ 13 ]。近年来，分子遗传学研究表明 GNAQ和 GNA11基因突变是促进细胞增生的早期事件 [ 10 ]； SF3B1基因突变具有中等转移风险，与晚期转移有关 [ 14 ]； EIF1AX基因突变患者预后较好，具有较长的无转移生存期 [ 10 ]。此外，Onken等 [ 13 ]通过对转移/非转移UM基因表达谱的差异分析筛选出12个差异表达基因(differentially expressed genes，DEGs)，并根据上述基因表达谱将肿瘤分为恶性程度低、不易转移的1型和恶性程度高、易转移的2型，相较基于肿瘤临床特征的预后评估更加准确、可靠。UM的发生和发展与基因突变和基因表达异常密切相关，而目前UM的临床分期仍以肿瘤大小和肿瘤所在区域为主要依据，且UM转移的诊断也主要依靠肝功能和影像学检测结果。因此，亟需鉴定出UM转移性相关的分子标志物，在UM微转移灶的潜伏期进行有效干预。此外，尽管既往研究已鉴定出UM影像学、组织学、染色体拷贝数变异水平上的预后指标，但目前仍缺乏分子遗传学水平的深入研究。本研究基于TCGA数据库对80个转移/非转移UM样本的基因突变、DEGs进行生物信息学分析，筛选并寻找新的UM预后指标，以期为探讨其发生和转移机制、提高患者远期预后提供参考。
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备注信息
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魏文斌，Email： mocdef.3ab61rtnibnewiew
B
所有作者均声明不存在利益冲突
C
北京市自然科学基金项目 (7204245)
北京市教育委员会科技发展计划一般项目 (KM202010025018)
北京市医院管理中心"青苗"计划专项经费项目 (QML20190202)
北京市东城区优秀人才培养计划项目 (2018)
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