Pan-Cancer Multiomics Analysis of TC2N Gene Suggests its Important Role(s) in Tumourigenesis of Many Cancers

Our plain-English summary of Pan-Cancer Multiomics Analysis of TC2N Gene Suggests its Important Role(s) in Tumourigenesis of Many Cancers, by M.A. Qureshi, S. Khan, M.S. Tauheed, et al (Asian Pacific Journal of Cancer Prevention, 2020).

The study

• Authors: M.A. Qureshi, S. Khan, M.S. Tauheed, S.A. Syed, I.D. Ujjan, A. Lail, S. Sharafat
• Journal: Asian Pacific Journal of Cancer Prevention
• Published: 2020;21(11):3199-3209
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

In plain English

This study did not examine asbestos. It was a secondary analysis of public cancer gene databases, mainly The Cancer Genome Atlas (TCGA) and the Genotype Tissue Expression (GTEx) database of normal tissue. It looked at a gene called TC2N across 33 tumour types, one of which was mesothelioma. The authors compared how active the gene was in tumours and in normal tissue, its promoter methylation (a chemical marking that can switch genes off), its link with patient survival, its correlation with other cancer-related genes, its likely protein partners and its mutations. Gene activity was significantly higher in five tumour types and lower in four. Mesothelioma was not among these nine. Survival was compared by splitting patients at the median TC2N level, and 6 of the 33 tumour types showed a significant difference. In mesothelioma, as in kidney renal clear cell carcinoma, sarcoma and skin cutaneous melanoma, patients with lower TC2N levels had shorter overall survival. The article's text does not give the number of mesothelioma patients or the size of that difference. The authors proposed that TC2N may play a role in several cancers and called for further studies to validate the findings.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Secondary (bioinformatic) analysis of publicly available cancer genomics databases (multiomics, pan-cancer)
• Who was studied: Tumour data sets for 33 tumour types in the TCGA database, including mesothelioma (MESO), compared with normal tissue from TCGA and the GTEx database. Patient numbers per tumour type and data dates are not given in the text.
• Exposure: No asbestos or other environmental or occupational exposure was studied. The factor examined was the level of TC2N gene expression (mRNA), with patients split into high and low groups at the median for survival analyses.
• Main results:
  • TC2N expression was significantly higher than in controls in cholangiocarcinoma, ovarian serous cystadenocarcinoma, rectal adenocarcinoma, stomach adenocarcinoma and thymoma.
  • TC2N expression was significantly lower than in controls in pheochromocytoma and paraganglioma, skin cutaneous melanoma, thyroid carcinoma and uterine carcinosarcoma.
  • Of the 33 tumour types, 6 showed a significant relationship between TC2N levels and overall survival.
  • Lower TC2N expression was associated with shorter overall survival in kidney renal clear cell carcinoma, mesothelioma, sarcoma and skin cutaneous melanoma. No patient counts, hazard ratios or p-values for these groups are given in the text.
  • Higher TC2N expression was associated with shorter overall survival in brain lower grade glioma and pancreatic adenocarcinoma.
  • In mesothelioma, a list of genes (beginning LRRK2, ADRB2, RND1) showed very strong positive correlation with TC2N expression.
  • The TC2N promoter was significantly hypermethylated in 13 tumour types and significantly hypomethylated in head and neck squamous cell carcinoma and kidney renal clear cell carcinoma. Mesothelioma was not listed.
  • 142 TC2N mutations were found across 145 cases in 18 tumour types: 73 missense, 33 synonymous, 12 stop gained, 11 in the 3'UTR and 13 other. The highest pathogenic mutation rates were in skin cutaneous melanoma, uterine corpus endometrial carcinoma, colon adenocarcinoma, bladder urothelial carcinoma and breast invasive carcinoma.
• The authors' conclusion: The authors proposed that TC2N may be an important player in the carcinogenesis, prognosis and therapeutics of several cancers, and said further clinical, in-vitro and/or in-vivo studies were needed to validate the findings.
• Limitations the authors state:
  • Clinical and sample details were not available for all tumour types, so only available parameters could be analysed.
  • It is unknown whether the mutations found cause cancer or result from it.
  • The findings need validation in further clinical and basic studies.

Topics

Medical terms in this study, explained in our Lexicon: Carcinogenesis, Lung Cancer, Somatic Mutation, Adenocarcinoma, Carcinoma, Prognosis, Mesothelioma, Sarcoma.

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