Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

Abstract Background: Alternative splicing (AS) is an important mechanism of regulating eukaryotic gene expression. Understanding the most common AS events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC.Methods: Publicly available RNA-seq data of 28 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify AS events using PSI and DEXSeq methods. Result: The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified AS events in 9 genes in CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6). Except for CHEK1, all other 8 splicing events were confirmed by TCGA data with 382 CRC tumors and 51 normal controls. The combination of three splicing events was used to build a logistic regression model that can predict sample type (CRC or normal) with near perfect performance (AUC=1). Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The AS features of the 9 genes are highly consistent with previous reports and/or relevant to cancer biology. Conclusions: The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

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Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

10.21203/rs.2.10736/v2 ◽

2019 ◽

Author(s):

Hongtao Jia ◽

Aili Wang ◽

Haifeng Lian ◽

Yuanyuan Shen ◽

Qian Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Alternative Splicing ◽

Cancer Biology ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Eukaryotic Gene ◽

Cancer Genome Atlas ◽

Alternative Splicing Events ◽

Therapeutic Tools

Abstract Alternative splicing is an important mechanism of regulating eukaryotic gene expression. Understanding the most common alternative splicing events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Publicly available RNA-seq data of 31 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify alternative splicing events using PSI and DEXSeq methods. The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified alternative splicing events in 10 genes marking the signature of CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6 and FBLN2-E9). Except for CHEK1, all other 9 splicing events were confirmed by TCGA data with 382 CRC tumors and 52 normal controls. Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The alternative splicing signatures of the 10 genes are highly consistent with previous reports and/or relevant to cancer biology. The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

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Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

10.21203/rs.2.10736/v3 ◽

2019 ◽

Author(s):

Haifeng Lian ◽

Aili Wang ◽

Yuanyuan Shen ◽

Qian Wang ◽

Zhenru Zhou ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Alternative Splicing ◽

Cancer Biology ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Eukaryotic Gene ◽

Cancer Genome Atlas ◽

Alternative Splicing Events ◽

Therapeutic Tools

Abstract Alternative splicing is an important mechanism of regulating eukaryotic gene expression. Understanding the most common alternative splicing events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Publicly available RNA-seq data of 31 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify alternative splicing events using PSI and DEXSeq methods. The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified alternative splicing events in 10 genes marking the signature of CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6 and FBLN2-E9). Except for CHEK1, all other 9 splicing events were confirmed by TCGA data with 382 CRC tumors and 52 normal controls. Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The alternative splicing signatures of the 10 genes are highly consistent with previous reports and/or relevant to cancer biology. The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

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Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

10.21203/rs.2.10736/v1 ◽

2019 ◽

Author(s):

Hongtao Jia ◽

Aili Wang ◽

Haifeng Lian ◽

Yuanyuan Shen ◽

Qian Wang ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Alternative Splicing ◽

Cancer Biology ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Eukaryotic Gene ◽

Cancer Genome Atlas ◽

Alternative Splicing Events ◽

Therapeutic Tools

Abstract Alternative splicing is an important mechanism of regulating eukaryotic gene expression. Understanding the most common alternative splicing events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Publicly available RNA-seq data of 31 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify alternative splicing events using PSI and DEXSeq methods. The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified alternative splicing events in 10 genes marking the signature of CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6 and FBLN2-E9). Except for CHEK1, all other 9 splicing events were confirmed by TCGA data with 382 CRC tumors and 52 normal controls. Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The alternative splicing signatures of the 10 genes are highly consistent with previous reports and/or relevant to cancer biology. The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

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Identification of a lncRNA prognostic signature-related to stem cell index and its significance in colorectal cancer

Future Oncology ◽

10.2217/fon-2020-1163 ◽

2021 ◽

Author(s):

Xiao-Cheng Wang ◽

Ya Liu ◽

Fei-Wu Long ◽

Liang-Ren Liu ◽

Chuan-Wen Fan

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Prognostic Markers ◽

The Cancer Genome Atlas ◽

Prognostic Signature ◽

Free Survival ◽

Cancer Genome Atlas ◽

Bioinformatic Approaches ◽

Cell Phenotypes ◽

The Relationship

Background: The relationship between long noncoding RNAs (lncRNAs) and the mRNA stemness index (mRNAsi) in colorectal cancer (CRC) is still unclear. Materials & methods: The mRNAsi, mRNAsi-related lncRNAs and their clinical significance were analyzed by bioinformatic approaches in The Cancer Genome Atlas (TCGA)-COREAD dataset. Results: mRNAsi was negatively related to pathological features but positively related to overall survival and recurrence-free survival in CRC. A five mRNAsi-related lncRNAs prognostic signature was further developed and showed independent prognostic factors related to overall survival in CRC patients, due to the five mRNAsi-related lncRNAs involved in several pathways of the cancer stem cells and malignant cancer cell phenotypes. Conclusion: The present study highlights the potential roles of mRNAsi-related lncRNAs as alternative prognostic markers.

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Downregulated SPINK4 is associated with poor survival in colorectal cancer

BMC Cancer ◽

10.1186/s12885-019-6484-5 ◽

2019 ◽

Vol 19 (1) ◽

Author(s):

Xiaojie Wang ◽

Qian Yu ◽

Waleed M. Ghareeb ◽

Yiyi Zhang ◽

Xingrong Lu ◽

...

Keyword(s):

Colorectal Cancer ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Expression Data ◽

Poor Survival ◽

Protein Levels ◽

Normal Tissues ◽

Human Protein Atlas ◽

Cancer Genome Atlas ◽

Independent Indicator

Abstract Background SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. Methods We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. Results SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. Conclusions We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.

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Expression Profiling of Calcium Channels and Calcium-Activated Potassium Channels in Colorectal Cancer

Cancers ◽

10.3390/cancers11040561 ◽

2019 ◽

Vol 11 (4) ◽

pp. 561 ◽

Cited By ~ 15

Author(s):

Ibrahim ◽

Dakik ◽

Vandier ◽

Chautard ◽

Paintaud ◽

...

Keyword(s):

Colorectal Cancer ◽

Potassium Channels ◽

Poor Prognosis ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Calcium Sensors ◽

Kca Channels ◽

Cancer Genome Atlas ◽

Calcium Activated Potassium Channels ◽

Ca2 Channels

Background: Colorectal cancer (CRC) is a highly devastating cancer. Ca2+-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca2+ channels and Ca2+-dependent potassium channels (KCa) with CRC using the transcriptional profile of their genes. Methods: We selected a total of 35 genes covering KCa channels KCNN1–4, KCNMA1 and their subunits KCNMB1–4, endoplasmic reticulum (ER) calcium sensors STIM1 and STIM2, Ca2+ channels ORAI1–3 and the family of cation channels TRP (TRPC1–7, TRPA1, TRPV1/2,4–6 and TRPM1–8). We analyzed their expression in two public CRC datasets from The Cancer Genome Atlas (TCGA) and GSE39582. Results: KCNN4 and TRPM2 were induced while KCNMA1 and TRPM6 were downregulated in tumor tissues comparing to normal tissues. In proximal tumors, STIM2 and KCNN2 were upregulated while ORAI2 and TRPM6 were downregulated. ORAI1 decreased in lymph node metastatic tumors. TRPC1 and ORAI3 predicted poor prognosis in CRC patients. Moreover, we found that ORAI3/ORAI1 ratio is increased in CRC progression and predicted poor prognosis. Conclusions: KCa and Ca2+ channels could be important contributors to CRC initiation and progression. Our results provide new insights on KCa and Ca2+ channels remodeling in CRC.

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Regulation of Long Non-coding RNA KCNQ1OT1 Network in Colorectal Cancer Immunity

Frontiers in Genetics ◽

10.3389/fgene.2021.684002 ◽

2021 ◽

Vol 12 ◽

Author(s):

Junjie Liu ◽

Wei Lv ◽

Shuling Li ◽

Jingwen Deng

Keyword(s):

Colorectal Cancer ◽

Immune Cell ◽

Cytotoxic T Cells ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Cerna Network ◽

Non Coding Rna ◽

Immune Cell Subsets ◽

Cancer Genome Atlas ◽

Cancer Tissues

Over the past few decades, researchers have become aware of the importance of non-coding RNA, which makes up the vast majority of the transcriptome. Long non-coding RNAs (lncRNAs) in turn constitute the largest fraction of non-coding transcripts. Increasing evidence has been found for the crucial roles of lncRNAs in both tissue homeostasis and development, and for their functional contributions to and regulation of the development and progression of various human diseases such as cancers. However, so far, only few findings with regards to functional lncRNAs in cancers have been translated into clinical applications. Based on multiple factors such as binding affinity of miRNAs to their lncRNA sponges, we analyzed the competitive endogenous RNA (ceRNA) network for the colorectal cancer RNA-seq datasets from The Cancer Genome Atlas (TCGA). After performing the ceRNA network construction and survival analysis, the lncRNA KCNQ1OT1 was found to be significantly upregulated in colorectal cancer tissues and associated with the survival of patients. A KCNQ1OT1-related lncRNA-miRNA-mRNA ceRNA network was constructed. A gene set variation analysis (GSVA) indicated that the expression of the KCNQ1OT1 ceRNA network in colorectal cancer tissues and normal tissues were significantly different, not only in the TCGA-COAD dataset but also in three other GEO datasets used as validation. By predicting comprehensive immune cell subsets from gene expression data, in samples grouped by differential expression levels of the KCNQ1OT1 ceRNA network in a cohort of patients, we found that CD4+, CD8+, and cytotoxic T cells and 14 other immune cell subsets were at different levels in the high- and low-KCNQ1OT1 ceRNA network score groups. These results indicated that the KCNQ1OT1 ceRNA network could be involved in the regulation of the tumor microenvironment, which would provide the rationale to further exploit KCNQ1OT1 as a possible functional contributor to and therapeutic target for colorectal cancer.

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Identification of lnc RNAs Related to Prognosis of Patients With Colorectal Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533033820962120 ◽

2020 ◽

Vol 19 ◽

pp. 153303382096212

Author(s):

Yuqi Sun ◽

Peng Peng ◽

Lanlan He ◽

Xueren Gao

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

High Expression ◽

Cox Regression Analysis ◽

Cancer Genome Atlas ◽

Score Model ◽

Prognostic Prediction

The purpose of this study was to identify long noncoding RNAs (lncRNAs) related to prognosis of patients with colorectal cancer (CRC) and develop a prognostic prediction model for CRC. Transcriptome data and survival information of CRC patients were downloaded from The Cancer Genome Atlas. The differentially expressed lncRNAs (DElncRNAs) between CRC and normal colorectal tissues were identified by the edgeR package. The association of DElncRNAs expression with prognosis of CRC patients was analyzed by the survival package. A nomogram predicting 3- and 5- year overall survival of CRC patients was drawn by the rms package. A total of 1046 DElncRNAs were identified, including 271 down-regulated and 775 up-regulated lncRNAs in CRC. Multivariate Cox regression analysis showed 10 lncRNAs related to the prognosis of CRC patients. Thereinto high expression of AC004009.1, LHX1-DT, ELFN1-AS1, AL136307.1, AC087379.2, RBAKDN and AC078820.1 was associated with poorer prognosis of CRC patients. High expression of LINC01055, AL590483.1 and AC008514.1 was associated with better prognosis of CRC patients. Furthermore, the risk score model developed based on the 10 lncRNAs could effectively predict overall survival of CRC patients. In conclusion, 10 prognostic biomarkers for CRC were identified, which would be helpful to understand the role of lncRNAs in CRC progression.

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Genome-wide methylation and expression profiling identify methylation-associated genes in colorectal cancer

Epigenomics ◽

10.2217/epi-2019-0133 ◽

2020 ◽

Vol 12 (1) ◽

pp. 19-36 ◽

Cited By ~ 1

Author(s):

Xiaohui Sun ◽

Diyu Chen ◽

Ziqi Jin ◽

Tianhui Chen ◽

Aifen Lin ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Expression Profiling ◽

The Cancer Genome Atlas ◽

Gene Overexpression ◽

Normal Tissues ◽

Atlas Data ◽

Genome Wide ◽

Cancer Genome Atlas ◽

Genome Atlas

Aim: To identify methylation-associated genes in the carcinogenesis of colorectal cancer (CRC). Materials & methods: Genome-wide patterns of DNA methylation and gene expression in CRC tissues and adjacent normal tissues were determined and further validated in The Cancer Genome Atlas data and Chinese CRC patients, respectively. Gene overexpression and knockdown cells were constructed to investigate their biological roles in CRC. Results: After validations, hypermethylation of eight genes were found to be correlated with their reduced transcription, and hypomethyaltion of three genes were associated with their upregulation. CADM3, CNRIP1, GRHL2, GRIA4, GSTM2 and NRXN1 were associated with the overall survival of CRC patients. CNRIP1 and GSTM2 were mainly responsible for the proliferation in CRC cells. Conclusion: A total of 11 genes may be promising biomarkers for CRC.

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