浆细胞瘤变异体易位1和MYC基因在泛癌中的表达及生存期预测价值分析

doi:10.16150/j.1671-2870.2022.04.012

摘要/Abstract

摘要：

目的：探讨浆细胞瘤变异体易位1（plasmacytoma variant translocation 1,PVT1）和MYC基因在泛癌组织中的表达水平,及其对患者生存期的预测价值。方法：从癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库获取31种共计10 016例癌症患者的临床资料以及转录组RNA测序数据,其中23种癌症组织标本有相应的癌旁正常组织对照。应用t检验比较PVT1、MYC基因在23种癌症组织与癌旁正常对照样本中的表达水平差异。采用Spearman相关性分析PVT1与MYC基因在31种癌症中表达的相关性。应用Kaplan-Meier方法和Cox比例风险模型,分别在31种癌症中分析PVT1、MYC基因的表达水平与患者总体生存期的关系。结果：PVT1的表达水平在19种癌症组织中显著增高（P<0.05）;在2种癌症组织中显著降低（P<0.05）。MYC的表达水平在7种癌症组织中显著升高（P<0.05）;在6种癌症组织中降低（P<0.05）。相关性分析发现,在约87%（27/31）的癌症类型中,PVT1与MYC基因的表达水平呈正相关（Rho>0, P<0.01）。总体生存期分析表明,PVT1相对高表达在膀胱尿路上皮细胞癌、乳腺浸润癌、肾上腺皮质癌、肾透明细胞癌、乳头状肾细胞癌、低级别胶质瘤、前列腺癌、睾丸生殖细胞肿瘤以及葡萄膜黑色素瘤中与较短的总体生存期显著相关（log-rank P<0.05）;MYC基因相对高表达在肾上腺皮质癌、膀胱尿路上皮细胞癌、宫颈鳞状细胞癌、头颈部鳞状细胞癌、乳头状肾细胞癌、卵巢浆液性囊腺癌、胰腺癌以及肉瘤中与较短的总体生存期显著相关（log-rank P<0.05）,而在低级别胶质瘤及直肠腺癌中,MYC基因相对高表达组的总体生存期显著长于相对低表达组（log-rank P<0.05）。结论：PVT1在癌症组织中表达升高相比MYC基因而言更具有普遍性。在多种癌症中,PVT与MYC基因的表达相关,提示两者在功能调控中可能存在联系。此外,在9种癌症中,PVT1相对高表达患者的总体生存期较短,而MYC基因的表达情况在不同癌症中对患者总体生存期的影响存在差异。

关键词: 浆细胞瘤变异体易位1基因, MYC基因, 肿瘤, 生存期

Abstract:

Objective: To explore the expression levels and survival prediction of plasmacytoma variant translocation 1 (PVT1) and MYC gene in pan-cancer. Methods: The clinic data and RNA-seq data from 31 types of cancer tissues totaling 10 016 cases were retrieved from The Cancer Genome Atlas (TCGA) database, among which 23 types of cancer with adjacent tissues as normal controls. Student t-tests were used to analyze the significant differences of PVT1 or MYC gene expression levels between cancer tissues and corresponding normal controls. Spearman correlation was used to analyze the expression correlation between PVT1 and MYC in 31 types of cancer. The relationship between PVT1 or MYC expression and overall survival of 31 types of cancer patients was depicted by the Kaplan-Meier curve and Cox proportional hazards model. Results: =PVT1 expression was highly expressed in 19 types of cancer(P<0.05) and lowly expressed in 2 types of cancer (P<0.05). MYC expression was significantly upregulated in 7 types of cancer (P<0.05) and downregulated in 6 types of cancer (P<0.05). Expression correlation analysis presented that PVT1 expression was positively correlated with MYC in about 87% (27/31) types of cancer (Rho>0, P<0.01). Finally, survival analysis showed that relatively high expression of PVT1 was significantly associated with shorter overall survival in bladder urothelial carcinoma, breast invasive carcinoma, adrenocortical carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, lower grade glioma, prostate adenocarcinoma, testicular germ cell tumors and uveal melanoma (log-rank P<0.05). The relatively high expression group of MYC was significantly correlated with shorter overall survival in adrenocortical carcinoma, bladder urothelial carcinoma, cervical squamous cell carcinoma, head and neck squamous cell carcinoma, renal papillary cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma and sarcoma (log-rank P<0.05), while was associated with long-time survival in lower grade glioma and rectum adenocarcinoma (log-rank P<0.05). Conclusions: The increased expression of PVT1 in pan-cancer is more prevalent than that of MYC. The positive correlation between PVT1 and MYC indicates a potential regulatory relationship in cancers. Furthermore, the relatively high expression of PVT1 has a poor effect on the overall survival of patients in 9 types of cancer, while the expression level of MYC presents different effects on the overall survival of patients in various cancers.

Key words: Plasmacytoma variant translocation 1 gene, MYC gene, Tumor, Survival time

中图分类号:

R541.7

马雪菲, 王学锋, 王侃侃. 浆细胞瘤变异体易位1和MYC基因在泛癌中的表达及生存期预测价值分析[J]. 诊断学理论与实践, 2022, 21(04): 490-496.

MA Xuefei, WANG Xuefeng, WANG Kankan. Pan-cancer analysis of plasmacytoma variant translocation 1 and MYC gene expression pattern and survival prediction[J]. Journal of Diagnostics Concepts & Practice, 2022, 21(04): 490-496.

图/表 5

图1

表1

图2

图3

表2

参考文献 25

[1]	Jiang N, Zhang X, Gu X, et al. Progress in understanding the role of lncRNA in programmed cell death[J]. Cell Death Discov, 2021, 7(1):30. doi: 10.1038/s41420-021-00407-1 pmid: 33558499
[2]	Wang W, Min L, Qiu X, et al. Biological function of long non-coding RNA (LncRNA) xist[J]. Front Cell Dev Biol, 2021, 9:645647.
[3]	McCabe EM, Rasmussen TP. lncRNA involvement in cancer stem cell function and epithelial-mesenchymal transitions[J]. Semin Cancer Biol, 2021, 75:38-48. doi: 10.1016/j.semcancer.2020.12.012 pmid: 33346133
[4]	Jin K, Wang S, Zhang Y, et al. Long non-coding RNA PVT1 interacts with MYC and its downstream molecules to synergistically promote tumorigenesis[J]. Cell Mol Life Sci, 2019, 76(21):4275-4289. doi: 10.1007/s00018-019-03222-1 pmid: 31309249
[5]	Tseng YY, Moriarity BS, Gong W, et al. PVT1 dependence in cancer with MYC copy-number increase[J]. Nature, 2014, 512(7512):82-86. doi: 10.1038/nature13311 URL
[6]	Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses[J]. Neoplasia, 2017, 19(8):649-658. doi: S1476-5586(17)30179-3 pmid: 28732212
[7]	Li B, Severson E, Pignon JC, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy[J]. Genome Biol, 2016, 17(1):174. doi: 10.1186/s13059-016-1028-7 pmid: 27549193
[8]	Li T, Fan J, Wang B, et al. TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells[J]. Cancer Res, 2017, 77(21):e108-e110. doi: 10.1158/0008-5472.CAN-17-0307 URL
[9]	Li T, Fu J, Zeng Z, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells[J]. Nucleic Acids Res, 2020, 48(W1):W509-W514. doi: 10.1093/nar/gkaa407 URL
[10]	Tang Z, Li C, Kang B, et al. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res, 2017, 45(W1):W98-W102. doi: 10.1093/nar/gkx247 URL
[11]	Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, et al. The cancer genome atlas pan-cancer analysis project[J]. Nat Genet, 2013, 45(10):1113-1120. doi: 10.1038/ng.2764 pmid: 24071849
[12]	Espinoza I, Agarwal S, Reddy A, et al. Expression of trefoil factor 3 is decreased in colorectal cancer[J]. Oncol Rep, 2021, 45(1):254-264. doi: 10.3892/or.2020.7829 pmid: 33210724
[13]	Huang S, Li D, Zhuang L, et al. Identification of Arp2/3 complex subunits as prognostic biomarkers for hepatocellular carcinoma[J]. Front Mol Biosci, 2021, 8:690151. doi: 10.3389/fmolb.2021.690151 URL
[14]	Luan W, Ding Y, Ma S, et al. Long noncoding RNA LIN 00518 acts as a competing endogenous RNA to promote the metastasis of malignant melanoma via miR-204-5p/AP1S2 axis[J]. Cell Death Dis, 2019, 10(11):855. doi: 10.1038/s41419-019-2090-3 URL
[15]	Yang YR, Zang SZ, Zhong CL, et al. Increased expression of the lncRNA PVT1 promotes tumorigenesis in non-small cell lung cancer[J]. Int J Clin Exp Pathol, 2014, 7(10):6929-6935.
[16]	Guo J, Hao C, Wang C, et al. Long noncoding RNA PVT1 modulates hepatocellular carcinoma cell proliferation and apoptosis by recruiting EZH2[J]. Cancer Cell Int, 2018, 18:98. doi: 10.1186/s12935-018-0582-3 pmid: 30008615
[17]	Tang J, Li Y, Sang Y, et al. LncRNA PVT1 regulates triple-negative breast cancer through KLF5/beta-catenin signaling[J]. Oncogene, 2018, 37(34):4723-4734. doi: 10.1038/s41388-018-0310-4 pmid: 29760406
[18]	Zhao J, Du P, Cui P, et al. LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer[J]. Oncogene, 2018, 37(30):4094-4109. doi: 10.1038/s41388-018-0250-z pmid: 29706652
[19]	Fang J, Huang J. Clinical significance of the expression of long non-coding RNA PVT1 in glioma[J]. Cancer Biomark, 2019, 24(4):509-513. doi: 10.3233/CBM-182253 pmid: 30909189
[20]	Wu H, Wei M, Jiang X, et al. lncRNA PVT1 Promotes tumorigenesis of colorectal cancer by stabilizing miR-16-5p and interacting with the VEGFA/VEGFR1/AKT Axis[J]. Mol Ther Nucleic Acids, 2020, 20:438-450. doi: 10.1016/j.omtn.2020.03.006 URL
[21]	Zhou C, Yi C, Yi Y, et al. LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modula-ting the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes[J]. Mol Cancer, 2020, 19(1):118. doi: 10.1186/s12943-020-01237-y URL
[22]	Schaub FX, Dhankani V, Berger AC, et al. Pan-cancer alterations of the MYC oncogene and its proximal network across the cancer genome atlas[J]. Cell Syst, 2018, 6(3):282-300. doi: S2405-4712(18)30097-8 pmid: 29596783
[23]	Duffy MJ, O'Grady S, Tang M, et al. MYC as a target for cancer treatment[J]. Cancer Treat Rev, 2021, 94:102154.
[24]	Shigeyasu K, Toden S, Ozawa T, et al. The PVT1 lncRNA is a novel epigenetic enhancer of MYC, and a promising risk-stratification biomarker in colorectal cancer[J]. Mol Cancer, 2020, 19(1):155. doi: 10.1186/s12943-020-01277-4 pmid: 33148262
[25]	Zhang MX, Zhang LZ, Fu LM, et al. Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis[J]. Oncogene, 2021, 40(37):5639-5650. doi: 10.1038/s41388-021-01971-7 URL

肿瘤类型	英文全称	中文名称	正常样本数量	肿瘤样本数量	表达差异P值	肿瘤中表达
BLCA	Bladder urothelial carcinoma	膀胱尿路上皮细胞癌	19	414	<0.001	升高
BRCA	Breast invasive carcinoma	乳腺浸润癌	113	1 102	<0.001	升高
CESC	Cervical squamous cell carcinoma	宫颈鳞状细胞癌	3	304	<0.001	升高
CHOL	Cholangiocarcinoma	胆管癌	9	36	<0.001	升高
COAD	Colon adenocarcinoma	结肠腺癌	41	478	<0.001	升高
ESCA	Esophageal carcinoma	食管癌	11	161	<0.001	升高
GBM	Glioblastoma multiforme	多形性胶质母细胞瘤	5	156	<0.001	升高
HNSC	Head and neck squamous cell carcinoma	头颈部鳞状细胞癌	44	500	<0.001	升高
KICH	Kidney chromophobe	肾嫌色细胞癌	24	65	0.022	升高
KIRC	Kidney renal clear cell carcinoma	肾透明细胞癌	72	538	<0.001	升高
KIRP	Kidney renal papillary cell carcinoma	乳头状肾细胞癌	32	288	<0.001	升高
LIHC	Liver hepatocellular carcinoma	肝细胞癌	50	371	<0.001	升高
LUAD	Lung adenocarcinoma	肺腺癌	59	533	<0.001	升高
LUSC	Lung squamous cell carcinoma	肺鳞状细胞癌	49	502	<0.001	升高
PAAD	Pancreatic adenocarcinoma	胰腺癌	4	177	0.762	无统计学意义
PRAD	Prostate adenocarcinoma	前列腺癌	51	498	<0.001	升高
PCPG	Pheochromocytoma and paraganglioma	嗜铬细胞瘤和副神经节瘤	3	178	0.001	降低
READ	Rectum adenocarcinoma	直肠腺癌	10	166	<0.001	升高
SARC	Sarcoma	肉瘤	2	259	0.178	无统计学意义
STAD	Stomach adenocarcinoma	胃腺癌	32	375	<0.001	升高
THCA	Thyroid carcinoma	甲状腺癌	58	502	0.046	降低
THYM	Thymoma	胸腺瘤	2	119	<0.001	升高
UCEC	Uterine corpus endometrial carcinoma	子宫内膜癌	35	551	<0.001	升高

Cancer types	中文名称	数量（相对高表达组）	数量（相对低表达组）	Log-rank P值	HR (high)	P (HR)值
ACC	肾上腺皮质癌	38	38	1.7E-4	4.9	6.3E-4
BLCA	膀胱尿路上皮细胞癌	201	201	8.8E-3	1.5	9.2E-3
CESC	宫颈鳞状细胞癌	146	146	3.9E-3	2	4.6E-3
HNSC	头颈部鳞状细胞癌	259	259	0.028	1.3	0.029
KIRP	乳头状肾细胞癌	141	141	0.041	1.9	0.046
LGG	低级别胶质瘤	257	257	2.6E-3	0.58	2.9E-3
OV	卵巢浆液性囊腺癌	212	212	0.029	1.3	0.029
PAAD	胰腺癌	89	89	8.5E-3	1.7	9.1E-3
READ	直肠腺癌	46	46	0.014	0.29	0.021
SARC	肉瘤	131	131	0.004	1.8	4.7E-3