Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer.
Alternative splicing (AS)
Colorectal cancer (CRC)
Metastasis
RNA-seq
TCGA
Journal
BMC gastroenterology
ISSN: 1471-230X
Titre abrégé: BMC Gastroenterol
Pays: England
ID NLM: 100968547
Informations de publication
Date de publication:
05 Jun 2020
05 Jun 2020
Historique:
received:
06
06
2019
accepted:
30
04
2020
entrez:
7
6
2020
pubmed:
7
6
2020
medline:
19
3
2021
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
RESULTS
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
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.
Identifiants
pubmed: 32503434
doi: 10.1186/s12876-020-01288-x
pii: 10.1186/s12876-020-01288-x
pmc: PMC7275609
doi:
Substances chimiques
Biomarkers, Tumor
0
COL6A3 protein, human
0
Collagen Type VI
0
Protein Isoforms
0
HKDC1 protein, human
EC 2.7.1.1
Hexokinase
EC 2.7.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
171Subventions
Organisme : Natural Science Foundation of Shangdong (CN)
ID : ZR2015LH083
Références
Oncotarget. 2014 Feb 15;5(3):667-78
pubmed: 24525428
Scand J Gastroenterol. 1998 Mar;33(3):301-9
pubmed: 9548625
Jpn J Cancer Res. 1995 Mar;86(3):292-7
pubmed: 7538103
Br J Surg. 1997 Mar;84(3):363-7
pubmed: 9117309
Cancer Cell. 2018 Aug 13;34(2):211-224.e6
pubmed: 30078747
PLoS One. 2015 Jan 12;10(1):e0116929
pubmed: 25581376
Biochem Biophys Res Commun. 2016 Jun 10;474(4):673-679
pubmed: 27155152
Tumori. 2013 Jan-Feb;99(1):88-92
pubmed: 23549006
Leukemia. 2018 May;32(5):1081-1093
pubmed: 29467484
Front Oncol. 2018 Nov 20;8:537
pubmed: 30524964
Mol Carcinog. 2012 Feb;51(2):165-73
pubmed: 21480394
Nucleic Acids Res. 2015 May 26;43(10):5130-44
pubmed: 25908786
BMC Genomics. 2016 Dec 28;17(Suppl 14):1011
pubmed: 28105922
Elife. 2016 May 11;5:
pubmed: 27166517
Cancer Sci. 2013 Feb;104(2):149-56
pubmed: 23113893
Cancer Biol Ther. 2007 Jul;6(7):1121-9
pubmed: 17611409
Mol Cancer. 2017 Jan 30;16(1):8
pubmed: 28137272
Oncogene. 2017 Aug 31;36(35):5035-5044
pubmed: 28459462
J Cell Biochem. 2012 Jul;113(7):2319-29
pubmed: 22345078
PLoS One. 2016 May 06;11(5):e0155160
pubmed: 27152521
Biochim Biophys Acta Mol Cell Res. 2018 Feb;1865(2):259-272
pubmed: 29138007
Int J Cancer. 2019 Feb 15;144(4):841-847
pubmed: 30121958
Oncotarget. 2016 Jul 19;7(29):45538-45546
pubmed: 27323782
Eur J Cancer. 1998 Jun;34(7):1099-1104
pubmed: 9849461
Int J Mol Sci. 2017 Dec 28;19(1):
pubmed: 29283381
Bioinformatics. 2014 Mar 15;30(6):748-52
pubmed: 24162464
Nature. 2008 Nov 27;456(7221):470-6
pubmed: 18978772
Oncotarget. 2015 Oct 6;6(30):29929-46
pubmed: 26338966
Int J Cancer. 2019 Jul 15;145(2):494-502
pubmed: 30628725
Wiley Interdiscip Rev RNA. 2017 Mar;8(2):
pubmed: 27440103
Oncotarget. 2015 Nov 24;6(37):40370-84
pubmed: 26430961
Cancer. 2013 Nov 15;119(22):4003-11
pubmed: 23963810
Clin Cancer Res. 2008 Nov 1;14(21):6751-60
pubmed: 18980968
Carcinogenesis. 2014 Jun;35(6):1217-27
pubmed: 24403311
Pflugers Arch. 2018 Jul;470(7):995-1016
pubmed: 29536164
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
BMC Genomics. 2018 May 29;19(1):405
pubmed: 29843604
Int J Cancer. 2013 Aug 1;133(3):590-6
pubmed: 23354951
Oncotarget. 2015 Aug 21;6(24):20312-26
pubmed: 26015410
J Clin Invest. 2010 Apr;120(4):1178-91
pubmed: 20335658
Cell Rep. 2017 Aug 29;20(9):2215-2226
pubmed: 28854369
Wiley Interdiscip Rev RNA. 2018 Jul;9(4):e1476
pubmed: 29693319
Br J Cancer. 2014 Nov 11;111(10):1993-2002
pubmed: 25211665
Elife. 2017 Sep 08;6:
pubmed: 28884683
J Cancer. 2018 Apr 19;9(10):1754-1764
pubmed: 29805701
Curr Opin Genet Dev. 2018 Feb;48:16-21
pubmed: 29080552
EBioMedicine. 2018 Oct;36:183-195
pubmed: 30243491
Front Mol Biosci. 2018 Feb 12;5:12
pubmed: 29484299
Pathol Res Pract. 2019 Feb;215(2):272-277
pubmed: 30463804
Genome Res. 2012 Oct;22(10):2008-17
pubmed: 22722343
Cancer Lett. 2020 Mar 31;473:186-197
pubmed: 31560935
Nat Rev Drug Discov. 2012 Nov;11(11):847-59
pubmed: 23123942
CA Cancer J Clin. 2015 Mar;65(2):87-108
pubmed: 25651787
Oncol Rep. 2016 Dec;36(6):3627-3634
pubmed: 27805251
Oncol Rep. 2018 Jun;39(6):2527-2536
pubmed: 29620224
Surgery. 2011 Aug;150(2):306-15
pubmed: 21719059
Int J Mol Sci. 2018 Feb 11;19(2):
pubmed: 29439487
Brief Bioinform. 2013 Mar;14(2):178-92
pubmed: 22517427
Mol Cell Proteomics. 2008 Jul;7(7):1214-24
pubmed: 18353764