Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile
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PROVIDER: PRJNA433947 | ENA |
REPOSITORIES: ENA
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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: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 Microarray analysis was performed on 13 SSAs and 11 TAs. SSAs were from 4 males and 9 females (mean age of 75) and TAs were from 5 males and 6 females (mean age of 72). Samples were directly hybridised to each other (SSA versus TA) or to a pooled normal control (SSA versus control). A linear model (Smyth 2004) was fitted to the data bringing together the three contrasts: SSA versus control, TA versus control and SSA versus TA. Human OligoLibrary (Compugen Human Oligo Library (v1) containing 18861 60-mer oligonucleotides, representing approximately 16,000 unique genes) by the Adelaide Microarray Centre (Australia) was used. Slides were scanned using a GenePix 3000B scanner (Axon Instruments, Sunnydale, CA), and the Spot package (CSIRO, Australia) was used to identify spots and estimate fore- and background intensities (using a morphological opening background estimator) (Yang, Buckley et al. 2001; Ritchie 2004). Data analysis was performed in R (www.r-project.org) using the Limma package of Bioconductor (Gentleman, Carey et al. 2004; Smyth 2004). Loess print tip method was used to correct for dye-bias and intensity within each group of adjacent spots printed by one pin (Yang, Dudoit et al. 2002). Linear modelling was performed with the Limma package of Bioconductor (Smyth 2004).
2008-08-26 | E-GEOD-12514 | biostudies-arrayexpress
Project description:Screening and surveillance of colorectal cancers (CRCs) using advanced colonoscopy technologies have significantly reduced the incidence and mortality rates of CRCs in recent years. However, a significant portion of CRCs are still remained undiagnosed, especially those involving sessile serrated adenomas/polyps (SSA/P), most likely due to their flat shape and the excessive amounts of secreted mucin that cover the polyps, making them invisible for colonoscopy. Here, a potential alternative solution is the application of molecular markers enabling unambiguous characterization of SSPs. However, full implementation of this strategy requires availability of robust markers which are still lacking. In this work by comprehensive molecular analysis of several malignant and normal samples at the genome, methylome and transcriptome levels we show that activating mutation of BRAF-V600E drives the generation of a unique SSP-specific DNA methylation profile. As the result a robust set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples, are introduced. These markers can be of important clinical relevance, especially in early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing.
2018-04-09 | GSE110537 | GEO
Project description:Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile (WGBS data set)
| PRJNA433957 | ENA
Project description:Screening and surveillance of colorectal cancers (CRCs) using advanced colonoscopy technologies have significantly reduced the incidence and mortality rates of CRCs in recent years. However, a significant portion of CRCs are still remained undiagnosed, especially those involving sessile serrated adenomas/polyps (SSA/P), most likely due to their flat shape and the excessive amounts of secreted mucin that cover the polyps, making them invisible for colonoscopy. Here, a potential alternative solution is the application of molecular markers enabling unambiguous characterization of SSPs. However, full implementation of this strategy requires availability of robust markers which are still lacking. In this work by comprehensive molecular analysis of several malignant and normal samples at the genome, methylome and transcriptome levels we show that activating mutation of BRAF-V600E drives the generation of a unique SSP-specific DNA methylation profile. As the result a robust set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples, are introduced. These markers can be of important clinical relevance, especially in early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing.
2018-04-09 | GSE110535 | GEO
Project description:Screening and surveillance of colorectal cancers (CRCs) using advanced colonoscopy technologies have significantly reduced the incidence and mortality rates of CRCs in recent years. However, a significant portion of CRCs are still remained undiagnosed, especially those involving sessile serrated adenomas/polyps (SSA/P), most likely due to their flat shape and the excessive amounts of secreted mucin that cover the polyps, making them invisible for colonoscopy. Here, a potential alternative solution is the application of molecular markers enabling unambiguous characterization of SSPs. However, full implementation of this strategy requires availability of robust markers which are still lacking. In this work by comprehensive molecular analysis of several malignant and normal samples at the genome, methylome and transcriptome levels we show that activating mutation of BRAF-V600E drives the generation of a unique SSP-specific DNA methylation profile. As the result a robust set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples, are introduced. These markers can be of important clinical relevance, especially in early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing.
2018-04-09 | GSE110536 | GEO
Project description:Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile (Exome-seq data set)
| PRJNA433956 | ENA
Project description:Active BRAF-V600E is the key player in generation of a sessile serrated polyp-specific DNA methylation profile (RNA-seq data set)
| PRJNA433955 | ENA
Project description:We aimed to identify epigenetic alterations associated with the development of traditional serrated adenomas (TSAs). Through DNA methylation analysis with HumanMethylation450 BeadChip in TSAs and sessile serrated adenoma/polyp (SSA/Ps), we identified DNA methylation specifically associated with TSA development.
2018-01-01 | GSE96540 | GEO
Project description:Background: Sessile serrated polyps (SSPs) have emerged as important precursors for a large number of sporadic colorectal cancers. They are difficult to detect during colonoscopy due to their flat shape and the excessive amounts of secreted mucin that cover the polyps. The underlying genetic and epigenetic basis for the emergence of SSPs is largely unknown with existing genetic studies confined to a limited number of oncogenes and tumor suppressors. A full characterization of the genetic and epigenetic landscape of SSPs would provide insight into their origin and potentially offer new biomarkers useful for detection of SSPs in stool samples.Methods: We used a combination of genome-wide mutation detection, exome sequencing and DNA methylation profiling (via methyl-array and whole-genome bisulfite sequencing) to analyze multiple samples of sessile serrated polyps and compared these to familial adenomatous polyps.Results: Our analysis revealed BRAF-V600E as the sole recurring somatic mutation in SSPs with no additional major genetic mutations detected. The occurrence of BRAF-V600E was coincident with a unique DNA methylation pattern revealing a set of DNA methylation markers showing significant (~3 to 30 fold) increase in their methylation levels, exclusively in SSP samples. These methylation patterns effectively distinguished sessile serrated polys from adenomatous polyps and did so more effectively than parallel gene expression profiles.Conclusions: This study provides an important example of a single oncogenic mutation leading to reproducible global DNA methylation changes. These methylated markers are specific to SSPs and could be of important clinical relevance for the early diagnosis of SSPs using non-invasive approaches such as fecal DNA testing.
| S-EPMC5873940 | biostudies-literature