Department of Pathology, Dow International Medical College, Dow University of Health Sciences Karachi, Pakistan.
Department of Oral Pathology, Dow Dental College, Dow University of Health Sciences, Karachi, Pakistan.
Asian Pac J Cancer Prev. 2020 Nov 1;21(11):3199-3209. doi: 10.31557/APJCP.2020.21.11.3199.
Role of TC2N in carcinogenesis has been largely unfathomed until recently when it was identified as a novel oncogene in lung cancer. Subsequently, a tumour suppressor role of TC2N was reported in breast cancer. It is therefore highly relevant to investigate TC2N molecular partners/mechanisms on a larger scale including a wider range of tumour types.
We investigated TC2N mRNA expression, its promoter methylation levels, effects of TC2N transcription on overall patient survival, somatic mutations in TC2N gene and correlation between TC2N mRNA expression and other cancer genes in pan-cancer by using data available from the Cancer Genome Atlas (TCGA) and the Genotype Tissue Expression (GTEx) databases.
TC2N mRNA expression was differentially regulated in 9/33 TCGA tumour types. Of these 9 tumours, 5 tumour types (cholangiocarcinoma, ovarian-serous-cystadenocarcinoma, rectal-adenocarcinoma, stomach-adenocarcinoma and thymoma) had significantly higher TC2N mRNA expression while 4 (pheochromocytoma-and-paraganglioma, skin-cutaneous-melanoma, thyroid-carcinoma and uterine-carcinosarcoma) had significantly lower TC2N mRNA expression compared to matched and normal controls. TC2N promoter was hypermethylated in most cancers while hypomethylated in head-and-neck-squamous-cell-carcinoma and kidney-renal-clear-cell carcinoma. TC2N transcription was positively correlated with transcription of several other cancer genes including genes from Myc, cell-cycle, Nrf2, Wnt, PI3K, Hippo, Notch, TGFβ and RAS/RTK pathways. Poor prognosis was associated with higher TC2N mRNA levels in pancreatic-adenocarcinoma and brain-lower-grade-glioma and lower TC2N mRNA levels in kidney-renal-clear-cell-carcinoma, mesothelioma, sarcoma and skin-cutaneous melanoma. Functional protein partners of TC2N were identified as STX2, SMEK1, SMEK2, STXBP5, SCARA5, MMRN1, CATSPER2, CATSPERB, CLEC4M and STAB2. Many of these proteins are key players in carcinogenesis of various cancers. Highest pathogenic somatic mutation rates in TC2N were found in skin-cutaneous-melanoma, uterine-corpus-endometrial-carcinoma, colon-endocervical-adenocarcinoma, bladder-urothelial-carcinoma and breast-invasive-carcinoma.
Our findings unravel several un-explored avenues related to the role of TC2N in tumourigenesis of several cancers, suggesting TC2N as an important player and a potential candidate for tumour-therapy.
TC2N 作为一种新型癌基因，在肺癌中的作用直到最近才被广泛研究。随后，有报道称 TC2N 在乳腺癌中具有肿瘤抑制作用。因此，在更大范围内研究 TC2N 的分子伴侣/机制，包括更广泛的肿瘤类型，是非常相关的。
我们通过使用癌症基因组图谱（TCGA）和基因型组织表达（GTEx）数据库中可用的数据，研究了 TC2N mRNA 表达、其启动子甲基化水平、TC2N 转录对整体患者生存的影响、TC2N 基因的体细胞突变以及 TC2N mRNA 表达与泛癌中其他癌症基因的相关性。
TC2N mRNA 表达在 9/33 种 TCGA 肿瘤类型中存在差异调节。在这 9 种肿瘤中，5 种肿瘤（胆管癌、卵巢浆液性囊腺癌、直肠腺癌、胃腺癌和胸腺瘤）的 TC2N mRNA 表达显著升高，而 4 种肿瘤（嗜铬细胞瘤和副神经节瘤、皮肤黑色素瘤、甲状腺癌和子宫癌肉瘤）的 TC2N mRNA 表达显著低于匹配和正常对照。TC2N 启动子在大多数癌症中呈高甲基化，而在头颈部鳞状细胞癌和肾透明细胞癌中呈低甲基化。TC2N 转录与其他几种癌症基因的转录呈正相关，包括 Myc、细胞周期、Nrf2、Wnt、PI3K、Hippo、Notch、TGFβ和 RAS/RTK 途径的基因。在胰腺腺癌和脑低级别胶质瘤中，较高的 TC2N mRNA 水平与不良预后相关，而在肾透明细胞癌、间皮瘤、肉瘤和皮肤黑色素瘤中，较低的 TC2N mRNA 水平与不良预后相关。TC2N 的功能蛋白伴侣被鉴定为 STX2、SMEK1、SMEK2、STXBP5、SCARA5、MMRN1、CATSPER2、CATSPERB、CLEC4M 和 STAB2。这些蛋白中的许多都是各种癌症发生的关键因素。在 TC2N 中发现最高的致病性体细胞突变率的癌症有皮肤黑色素瘤、子宫体子宫内膜癌、结肠宫颈腺癌、膀胱癌和乳腺浸润性癌。
我们的研究结果揭示了与 TC2N 在几种癌症发生中的作用相关的几个尚未探索的途径，表明 TC2N 是一个重要的参与者和潜在的肿瘤治疗候选者。
