Project description:In murine models, we find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation and senescence. This corresponds to inefficient tumor formation in oncogenic BRAF mouse models of colon cancer. By reducing levels of differentiation in the gut via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2), stem cell activity is restored in BRAFV600E intestines, and the oncogenic capacity of mutant BRAF is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these findings help resolve the conditions necessary for BRAF-driven colon cancer initiation.
Project description:Colorectal cancer, one of the most frequent types of malignancy in the Western world, develops through a multi-step process. The main pathways establishing transformation of normal mucosa to invasive carcinoma include chromosomal instability (CIN), microsatellite instability (MSI) or epigenetic silencing through the CpG Island Methylator Phenotype (CIMP). These pathways have distinct clinical, pathological and genetic characteristics. In general, altered cell surface glycosylation has been linked to colorectal cancer progression, however the impact of MSI-specific pathways on the glycosylation machinery of MSI colon cancer cells has not been investigated yet. In a recent study (Patsos et al., 2009) we have shown that MSI-specific mutations induce marked alterations in cell surface glycosylation, indicating specific changes in the expression of glyco-genes. Therefore the purpose of our experiment is to define these changes by glyco-gene chip analysis.
Project description:To investigate whether lifestyle factors modulate the stability of gene promoter methylation in the normal aging colonic mucosa, we performed genome-scale DNA methylation profiling of 178 normal colon biopsies using the Illumina Infinium DNA methylation assay, which assesses the DNA methylation status of 27,578 CpG sites located at the promoter regions of 14,495 protein-coding genes. We identified Aspirin use and hormonal replacement therapy (HRT) suppress, whereas a high body mass index (BMI) and smoking promote age-related hyermethylation. Many of these loci modulated by lifestyle in the healthy colon mucosa coincide with loci hypermethylated in colorectal cancers and down-regulated in adenomas. The data show that lifestyle modulates the stability of DNA methylation in the aging colonic epithelium and thereby impacts the rate of evolution of cancer methylomes.
Project description:To investigate whether lifestyle factors modulate the stability of gene promoter methylation in the normal aging colonic mucosa, we performed genome-scale DNA methylation profiling of 178 normal colon biopsies using the Illumina Infinium DNA methylation assay, which assesses the DNA methylation status of 27,578 CpG sites located at the promoter regions of 14,495 protein-coding genes. We identified Aspirin use and hormonal replacement therapy (HRT) suppress, whereas a high body mass index (BMI) and smoking promote age-related hyermethylation. Many of these loci modulated by lifestyle in the healthy colon mucosa coincide with loci hypermethylated in colorectal cancers and down-regulated in adenomas. The data show that lifestyle modulates the stability of DNA methylation in the aging colonic epithelium and thereby impacts the rate of evolution of cancer methylomes. Bisulphite converted DNA from the 178 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
