دورية أكاديمية
أعرض في EDS

DNA methylation analysis of normal colon organoids from familial adenomatous polyposis patients reveals novel insight into colon cancer development.

التفاصيل البيبلوغرافية
العنوان: DNA methylation analysis of normal colon organoids from familial adenomatous polyposis patients reveals novel insight into colon cancer development.
المؤلفون: Devall MA; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Eaton S; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Ali MW; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Dampier CH; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Weisenberger D; Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA., Powell SM; Digestive Health Center, University of Virginia, Charlottesville, VA, USA., Li L; Department of Family Medicine, University of Virginia, Charlottesville, VA, USA., Casey G; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. gc8r@virginia.edu.; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. gc8r@virginia.edu.
المصدر: Clinical epigenetics [Clin Epigenetics] 2022 Aug 23; Vol. 14 (1), pp. 104. Date of Electronic Publication: 2022 Aug 23.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: BiomedCentral Country of Publication: Germany NLM ID: 101516977 Publication Model: Electronic Cited Medium: Internet ISSN: 1868-7083 (Electronic) Linking ISSN: 18687075 NLM ISO Abbreviation: Clin Epigenetics Subsets: MEDLINE
أسماء مطبوعة: Publication: Oct./Nov. 2011- : London : BiomedCentral
Original Publication: Berlin : Springer-Verlag
مواضيع طبية MeSH: Adenomatous Polyposis Coli*/genetics , Adenomatous Polyposis Coli*/pathology , Colonic Neoplasms*/genetics , Colorectal Neoplasms*/genetics, Adenomatous Polyposis Coli Protein/genetics ; DNA Methylation ; Genome-Wide Association Study ; Humans ; Organoids/pathology ; Tripartite Motif Proteins/genetics ; Ubiquitin-Protein Ligases/genetics
مستخلص: Background: Familial adenomatous polyposis (FAP) is an inherited colorectal cancer (CRC) syndrome resulting from germ line mutations in the adenomatous polyposis coli (APC) gene. While FAP accounts for less than 1% of all CRC cases, loss of APC expression is seen in > 80% of non-hereditary CRCs. To better understand molecular mechanisms underlying APC-driven CRC, we performed an epigenome-wide analysis of colon organoids derived from normal-appearing colons of FAP patients versus healthy subjects to identify differentially methylated regions (DMRs) that may precede the onset of CRC.
Results: We identified 358 DMRs when comparing colon organoids of FAP patients to those of healthy subjects (FDR < 0.05, |mean beta difference| = 5%). Of these, nearly 50% of DMRs were also differentially methylated in at least one of three CRC tumor and normal adjacent tissue (NAT) cohorts (TCGA-COAD, GSE193535 and ColoCare). Moreover, 27 of the DMRs mapped to CRC genome-wide association study (GWAS) loci. We provide evidence suggesting that some of these DMRs led to significant differences in gene expression of adjacent genes using quantitative PCR. For example, we identified significantly greater expression of five genes: Kazal-type serine peptidase inhibitor domain 1 (KAZALD1, P = 0.032), F-Box and leucine-rich repeat protein 8 (FBXL8, P = 0.036), TRIM31 antisense RNA 1 (TRIM31-AS1, P = 0.036), Fas apoptotic inhibitory molecule 2 (FAIM2, P = 0.049) and (Collagen beta (1-0)galactosyltransferase 2 (COLGALT2, P = 0.049). Importantly, both FBXL8 and TRIM31-AS1 were also significantly differentially expressed in TCGA-COAD tumor versus matched NAT, supporting a role for these genes in CRC tumor development.
Conclusions: We performed the first DNA methylome-wide analysis of normal colon organoids derived from FAP patients compared to those of healthy subjects. Our results reveal that normal colon organoids from FAP patients exhibit extensive epigenetic differences compared to those of healthy subjects that appear similar to those exhibited in CRC tumor. Our analyses therefore identify DMRs and candidate target genes that are potentially important in CRC tumor development in FAP, with potential implications for non-hereditary CRC.
(© 2022. The Author(s).)
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معلومات مُعتمدة: P20 CA233216 United States CA NCI NIH HHS; R01 CA143237 United States NH NIH HHS
فهرسة مساهمة: Keywords: Colon organoids; Colorectal cancer; DNA methylation; Familial adenomatous polyposis
المشرفين على المادة: 0 (Adenomatous Polyposis Coli Protein)
0 (Tripartite Motif Proteins)
EC 2.3.2.27 (TRIM31 protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
تواريخ الأحداث: Date Created: 20220823 Date Completed: 20220825 Latest Revision: 20230106
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC9396789
DOI: 10.1186/s13148-022-01324-5
PMID: 35999641
قاعدة البيانات: MEDLINE
الوصف
تدمد:1868-7083
DOI:10.1186/s13148-022-01324-5