BRAFV600E expression in intestinal tissue promotes a cholesterol metabolic gene signature that sustains hyperplasia and characterizes serrated colorectal neoplasia
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PROVIDER: PRJNA981142 | ENA |
REPOSITORIES: ENA
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Project description:BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis are poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
2023-09-07 | GSE234372 | GEO
Project description:BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis are poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
2023-09-27 | GSE236515 | GEO
Project description:BRAFV600E expression in intestinal tissue promotes a cholesterol metabolic gene signature that sustains hyperplasia and characterizes serrated colorectal neoplasia (RNA-Seq)
| PRJNA991517 | ENA
Project description:This study was conducted to explore the serum methylome of precancerous lesions belonging to the serrated pathway of colorectal carcinogenesis in a prospective multicentre cohort. Individuals were grouped into five main categories: (i) serrated adenocarcinoma (SAC), (ii) high-risk serrated polyps (HR-SP) comprising traditional serrated adenomas (TSA), sessile serrated lesions (SSL), and serrated polyps (SP) with dysplasia or ≥ 10 mm; (iii) high-risk hyperplastic polyps (HR-HP), defined as HP ≥ 10 mm; (iv) low-risk serrated lesions (LR-SL) including SP without dysplasia < 10 mm and HP < 10 mm; and (v) healthy individuals with no colorectal findings (NCF). First, epigenome-wide methylation levels were quantified in pooled cfDNA samples to characterize the differential methylation profile between no serrated neoplasia (NSN: NCF and LR-SL) and high-risk serrated lesions (HR-SL: HR-HP and HR-SP); concordance with tissue methylation levels was assessed using external datasets. Then, the pathway-specific cfDNA methylation signature was evaluated together with cfDNA pools from the conventional CRC pathway. cfDNA was extracted from serum samples and methylation measurements were assessed with the Infinium MethylationEPIC BeadChip. Data was mainly preprocessed and analyzed with R/Bioconductor packages.
2024-03-01 | GSE199173 | GEO
Project description:Abstract: Colonic cancers with a serrated morphology have been proposed to comprise a molecularly distinct tumor entity following an alternative pathway of genetic alterations independently of APC mutations. Here we demonstrate that intestinal cell specific expression of oncogenic K-rasG12D in mice induces serrated hyperplasia, which is characterized by p16ink4a overexpression and induction of senescence. Deletion of Ink4a/Arf in K-rasG12D expressing mice prevents senescence and leads to invasive, metastasizing carcinomas with morphological and molecular alterations comparable to human KRAS mutated serrated tumors. Thus, we suggest that oncogenic K-ras is sufficient to initiate an alternative, serrated pathway to colorectal cancer and hence propose RAS-RAF-MEK signaling apart from APC as an additional gatekeeper in colorectal tumor development.
2010-03-06 | GSE20647 | GEO
Project description:Serrated adenocarcinomas are morphologically different from conventional adenocarcinomas. The serrated pathway has recently been proposed to represent a novel mechanism of colorectal cancer (CRC) formation. However, whether they are biologically different and truly form a distinct subclass of CRC, is not known. This study shows that the gene expression profile of serrated and conventional CRCs differs from each others and that serrated CRCs are not only morphologically novel, but also biologically distinct subclass of CRC. Keywords: molecular classification
2006-07-28 | GSE4045 | GEO
Project description:Objective: Serrated colorectal cancer (CRC) accounts for approximately 25% of cases, and includes tumours that are amongst the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen activated kinase (MAPK) pathway gene, BRAF, and epigenetic modifications termed the CpG Island Methylator Phenotype (CIMP), leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein. Design: We utilise organoid culture combined with CRISPR/Cas9 genome engineering, to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair. Results: Targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not BrafV600E alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, Mlh1, led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting. Conclusion: We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.
2018-04-30 | GSE112774 | GEO
Project description:Profiling project of a panel of tubular adenoma and serrated adenoma patient material collected in the Academic Medical Center (AMC) in Amsterdam, The Netherlands. The aim of the study was to compare the expression profiles of different types of colon cancer precursor lesions (tubular versus serrated adenomas) and determine their correspondence with a set of colon cancer patient-derived profiles that have distinct clinical outcomes. 6 serrated adenomas and 7 tubular adenomas are profiled in this study.
2013-04-14 | E-GEOD-45270 | biostudies-arrayexpress
Project description:Sessile serrated adenomas are now recognized as precursor lesions of a substantial subset of colorectal cancers arising via a so-called “serrated pathway”. However, their biological markers remain to be defined. The aim of our study was to identify differentially expressed genes in sessile serrated adenomas, hyperplastic polyps and tubular adenomas. Gene expression analysis demonstrated molecular differences between polyp types. Further studies using QRT-PCR on Cathepsin E demonstrated a significantly (p< 0.05) higher expression in sessile serrated adenomas as compared to both other polyp types. Trefoil Factor 1, showed the same trend of expression for sessile serrated adenomas as compared to hyperplastic polyps, and was significantly higher in both polyps compared to tubular adenomas. Immunohistochemistry for both proteins demonstrated strong cytoplasmic staining of abnormal crypts in all sessile serrated adenomas while staining in tubular adenomas and hyperplastic polyps was weak and focal. BRAF and KRAS mutation analysis were employed to further validate polyp discrimination. The findings demonstrated the positive association of the BRAF mutation, V600E, with sessile serrated adenomas and KRAS mutations with tubular adenomas (P<0.05). This study demonstrates CTSE and TFF1 over-expression in sessile serrated adenomas compared to both hyperplastic polyps and tubular adenomas. Keywords: colonic polyp tissue comparison, linear modelling, SSA
2008-08-27 | GSE12514 | GEO
Project description:To further characterized the serrated pathway, we used the novel Digital Spatial Profiling (DSP) technology and its mRNA Cancer Transcriptome Atlas (CTA) panel, which includes over 1800 target gene, to investigate the underlying gene expression changes and pathways involved in sessile serrated lesion (SSL) and traditional serrated adenoma (TSA), two precancerous lesions to carcinoma in serrated pathway.
2023-12-31 | E-MTAB-12465 | biostudies-arrayexpress