Project description:Enhancer aberrations are beginning to emerge as a key feature of colorectal cancers, however, we have limited understanding of epigenomic patterns that distinguish tumors and underlying heterogeneity between tumors. Here, using epigenomic profiling of colorectal tumors, adenomas and normal colon tissues, we identify unique pattern of regulatory elements in colorectal cancer, which could reliably distinguish tumors from normal colon specimens. We define shared and unique enhancer elements during colorectal cancer progression using normal adjacent colon, adenomas and adenocarcinomas. We validate the functional nature of tumor-specific enhancers for important oncogenes such as ASCL2 and Fzd10. NMF clustering identified 4 epigenetic (EPIC) subtypes in colorectal cancer, which mimics consensus molecular subtypes (CMS)1, with an advantage of introducing a novel epigenetically-identifiable subtype with poor prognosis and survival. Based on this correlation, we defined and validated a combination therapeutic strategy of enhancer-blocking BETi with pathway specific inhibitor for 3 CMS subtypes. In conclusion, by comprehensive characterization of chromatin state patterns in colorectal tumors, we define epigenomic patterns during tumor evolution, heterogeneity of enhancers among patients and a combination therapy strategy for CMS-subgroups.
Project description:Enhancer aberrations are beginning to emerge as a key feature of colorectal cancers, however, we have limited understanding of epigenomic patterns that distinguish tumors and underlying heterogeneity between tumors. Here, using epigenomic profiling of colorectal tumors, adenomas and normal colon tissues, we identify unique pattern of regulatory elements in colorectal cancer, which could reliably distinguish tumors from normal colon specimens. We define shared and unique enhancer elements during colorectal cancer progression using normal adjacent colon, adenomas and adenocarcinomas. We validate the functional nature of tumor-specific enhancers for important oncogenes such as ASCL2 and Fzd10. NMF clustering identified 4 epigenetic (EPIC) subtypes in colorectal cancer, which mimics consensus molecular subtypes (CMS)1, with an advantage of introducing a novel epigenetically-identifiable subtype with poor prognosis and survival. Based on this correlation, we defined and validated a combination therapeutic strategy of enhancer-blocking BETi with pathway specific inhibitor for 3 CMS subtypes. In conclusion, by comprehensive characterization of chromatin state patterns in colorectal tumors, we define epigenomic patterns during tumor evolution, heterogeneity of enhancers among patients and a combination therapy strategy for CMS-subgroups.
Project description:Cancer cells utilize genetic and epigenetic aberrations for their excessive growth. Although we have sufficient understanding of the genomic alterations in colorectal cancer, we have incomplete knowledge of epigenomic aberrations and their impact on tumor growth. In order to comprehensively define the epigenetic patterns specific to colorectal cancer, we generated profiles for 6 histone modification marks, including H3K4me1 (enhancer), H3K27Ac (active enhancer), H3K9me3 (heterochromatin), H3K27me3 (polycomb repression), H3K79me2 (transcription) and H3K4me3 (promoter), using a high-throughput ChIP-Seq methodology developed in house applicable to frozen tumors. Chromatin state transitions specifically pointed to drastic changes in enhancer patterns, consistent with some prior studies. Furthermore, we identified the best combinatorial chromatin states that could most efficiently distinguish and predict CRC from normal colon. In a more detailed investigation into patterns of active enhancers using normal colon, adenomas and colorectal cancers, we identified specific changes in enhancers from normal tissue to these neoplastic lesions. Importantly, we noted gains of enhancers in a large number of genomic loci in colon cancer compared to adjacent normal tissues. In summary, we have identified aberrant enhancer gains as a major feature of colorectal cancer and propose this to be utilized as a therapeutic approach.
Project description:We present a meta-dataset comprising of a total of 1566 samples including both primary tumors and tumor-free colorectal tissues from 15 independent GEO datasets. To minimise inter-platform variation, only datasets generated from the GPL570 platform (Affymetrix Human Genome U133 Plus 2.0 Array) were processed to develop the meta-dataset. Using multiple open source R packages implemented in our previously developed bioinformatics pipeline, each dataset has been preprocessed with RMA normalisation, merged, and batch effect-corrected via Combat method. With increased sample size, the present meta-dataset serves an excellent 'discovery cohort' for discovering differentially expressed in diseased phenotype.
Project description:Response to drug therapy in individual colorectal cancer (CRC) patients is associated with tumor biology. Here we describe the genomic landscape of tumor samples of a homogeneous well-annotated series of patients with metastatic CRC of two phase III clinical trials, CAIRO and CAIRO2. DNA copy number aberrations of 349 patients are determined. Within three treatment arms, 194 chromosomal sub-regions are associated with progression free survival PFS (uncorrected single-test p-values < 0.005). These sub-regions are filtered for effect on mRNA expression, using an independent data set from The Cancer Genome Atlas (TCGA) which returned 171 genes. Three chromosomal regions are associated with a significant difference in PFS between treatment arms with or without irinotecan. One of these regions, 6q16.1-q21, correlates in vitro with sensitivity to SN-38, the active metabolite of irinotecan. This genomic landscape of metastatic CRC reveals a number of DNA copy number aberrations associated with response to drug therapy. aCGH data of colorectal cancers of patients from 2 clinical trials (CAIRO, CAIRO2). 105 patients were treated with capecitabine first line (CAIRO arm A), 111 patients were treated with capecitabine and irinotecan first line (CAIRO arm B), and 133 patients were treated with capecitabine, oxaliplatin and bevacizumab (CAIRO2 arm A).
Project description:We characterized the epigenetic landscape of human colorectal cancer (CRC). To this extent, we performed gene expression profiling using high throughput sequencing (RNA-seq) and genome wide binding/occupancy profiling (ChIP-seq) for histone modifications correlated to transcriptional activity, enhancers, elongation and repression (H3K4me3, H3K4me1, H3K27Ac, H3K36me3, H3K27me3) in patient-derived organoids (PDOs), and in normal and tumoral primary colon tissues. We also generated ChIP-seq data for transcription factors YAP/TAZ in human CRC PDOs.
Project description:We characterized the epigenetic landscape of human colorectal cancer (CRC). To this extent, we performed gene expression profiling using high throughput sequencing (RNA-seq) and genome wide binding/occupancy profiling (ChIP-seq) for histone modifications correlated to transcriptional activity, enhancers, elongation and repression (H3K4me3, H3K4me1, H3K27Ac, H3K36me3, H3K27me3) in patient-derived organoids (PDOs), and in normal and tumoral primary colon tissues. We also generated ChIP-seq data for transcription factors YAP/TAZ in human CRC PDOs.