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Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway.

ABSTRACT: To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high-methylation CRC. The methylation levels of six Group-1 and 14 Group-2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group-1 and Group-2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high-methylation CRC. But TSA showed low-methylation levels of Group-1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high-methylation CRC. High-methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p?

SUBMITTER: Sakai E

PROVIDER: S-EPMC4737347 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway.

Sakai Eiji E Fukuyo Masaki M Ohata Ken K Matsusaka Keisuke K Doi Noriteru N Mano Yasunobu Y Takane Kiyoko K Abe Hiroyuki H Yagi Koichi K Matsuhashi Nobuyuki N Fukushima Junichi J Fukayama Masashi M Akagi Kiwamu K Aburatani Hiroyuki H Nakajima Atsushi A Kaneda Atsushi A

International journal of cancer 20151112 7

To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high-methylation CRC. The methylation levels of six Group-1 and 14 Group-2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alt ...[more]

PMID: 26510091

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Project description:BackgroundDysregulation of erythropoietin-producing hepatoma (Eph) proteins in human cancers is extensively documented but not clear in colorectal cancer (CRC). In this study, we aimed to investigate the role of Notch signaling pathway and epigenetic modification of EPHB2 and EPHB4 expression in serrated neoplasia development.MethodsThe expression of EPHB2 and EPHB4 in CRC clinical specimens and cell lines were determined by immunohistochemistry, Western blot, and real-time PCR. Cell proliferation and invasion were evaluated by MTT and chamber kits, luciferase assay and co-immunoprecipitation were used to detect the transcriptional regulation and protein-protein interactions, respectively. The immunofluorescence assay was employed to confirm the subcellular location of Notch intracellular domain (NICD), and chromatin immunoprecipitation assay was implied to detect the modification types of H3K4me3 and H3K27me3. Mice xenograft model was used to detect the in vivo effects of EPHB2 and EPHB4 genes on cell growth.ResultsIn CRC clinical specimens and cell lines, we found that EPHB2 was significantly decreased, while EPHB4 was elevated in the CRC tissues, and these aberrant expression manners correlated with worse overall survival rates in the clinic. When the EPHB2 and EPHB4 expressions were manipulated by overexpression or knockdown in the SW620 cells, the cell proliferation and invasion were obviously suppressed, whereas EPHB2 knockdown or EPHB4 overexpression showed the opposite phenotypes. We also found that Notch signaling pathway was abnormally activated and treatment of Notch signaling ligand human Jagged1 peptide downregulated EPHB2 and upregulated EPHB4 in the SW620 cells, as well as promoted the chromatin modification protein Jumonji domain-containing protein-3 (JMJD3) cytonuclear trans-localization with the NICD, which indicated that NICD brought JMJD3 to the EPHB4 enhancer region to decrease the H3K27me3 level.ConclusionTaken together, we provide a new mechanistic option in understanding the role of Notch signaling and the roles of EPHB2 and EPHB4 in CRC.

Project description:Background and aimsApproximately 20%-30% of colorectal cancers (CRCs) arise from the serrated polyp pathway. CRC screening options have differential sensitivity to detect sessile serrated polyps (SSPs). We used the Colorectal Cancer and Adenoma Incidence and Mortality Microsimulation Model (CRC-AIM) to assess how the detection of SSPs impacts predicted life years gained (LYG), CRC incidence, and CRC mortality with multitarget stool DNA (mt-sDNA) or fecal immunochemical test (FIT) screening.MethodsA simulated cohort of average-risk US individuals underwent triennial mt-sDNA or annual FIT screening between ages 45-75 years. SSP-attributed CRCs were modeled at 0% (base case), 14.3%, 20%, and 30%, in combination with 4 adherence & attendance scenarios: S1: 100% stool-screening adherence/100% follow-up colonoscopy attendance after a positive stool test; S2: reported stool-screening adherence (mt-sDNA = 71%; FIT = 43%)/100% follow-up colonoscopy attendance; S3: reported stool-screening adherence/reported follow-up colonoscopy attendance (mt-sDNA = 72%; FIT = 47%); and S4: reported stool-screening adherence/72% follow-up colonoscopy attendance. Outcomes were per 1000 individuals. Sensitivity analyses used ranges of stool-screening adherence or follow-up attendance.ResultsAt S1, S2, S3, and S4, LYG with FIT at the base case (0% SSP-attributed CRC) was 346.7, 279.3, 126.6, and 196.1, respectively, and with mt-sDNA was 324.6, 311.8, 215.8, and 215.8, respectively. Among the 4 adherence/attendance scenarios, modeling SSP-attributed CRCs decreased LYG by 4.9-20.9 with FIT and 2.0-5.1 with mt-sDNA. At S3 and 30% SSP-attributable CRCs, mt-sDNA had 95.1 more LYG, 21.5% greater CRC incidence reduction, and 22.2% greater CRC mortality reduction than FIT.ConclusionIncorporating SSPs and real-world adherence into the CRC-AIM modeling analyses yielded more practice-relevant estimates of CRC screening outcomes and should be applied in future studies to afford more appropriate assessment of comparative effectiveness estimates between guideline-endorsed screening options.

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Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway.

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Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway.

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