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Promoter capture Hi-C-based identification of recurrent noncoding mutations in colorectal cancer.

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Date
2018-10
ICR Author
Law, Philip
Cornish, Alexander
Broderick, Peter
Houlston, Richard
Litchfield, Kevin
Author
Orlando, G
Law, PJ
Cornish, AJ
Dobbins, SE
Chubb, D
Broderick, P
Litchfield, K
Hariri, F
Pastinen, T
Osborne, CS
Taipale, J
Houlston, RS
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Type
Journal Article
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Abstract
Efforts are being directed to systematically analyze the non-coding regions of the genome for cancer-driving mutations 1-6 . cis-regulatory elements (CREs) represent a highly enriched subset of the non-coding regions of the genome in which to search for such mutations. Here we use high-throughput chromosome conformation capture techniques (Hi-C) for 19,023 promoter fragments to catalog the regulatory landscape of colorectal cancer in cell lines, mapping CREs and integrating these with whole-genome sequence and expression data from The Cancer Genome Atlas 7,8 . We identify a recurrently mutated CRE interacting with the ETV1 promoter affecting gene expression. ETV1 expression influences cell viability and is associated with patient survival. We further refine our understanding of the regulatory effects of copy-number variations, showing that RASL11A is targeted by a previously identified enhancer amplification 1 . This study reveals new insights into the complex genetic alterations driving tumor development, providing a paradigm for employing chromosome conformation capture to decipher non-coding CREs relevant to cancer biology.
URI
https://repository.icr.ac.uk/handle/internal/2956
DOI
https://doi.org/10.1038/s41588-018-0211-z
Collections
  • Genetics and Epidemiology
  • Molecular Pathology
Subject
Caco-2 Cells
Hela Cells
HT29 Cells
K562 Cells
Tumor Cells, Cultured
Chromosomes, Human
Humans
Colorectal Neoplasms
Cell Transformation, Neoplastic
DNA, Neoplasm
Codon, Nonsense
Computational Biology
Regulatory Sequences, Nucleic Acid
Nucleic Acid Conformation
Gene Frequency
Databases, Genetic
Promoter Regions, Genetic
Hep G2 Cells
High-Throughput Nucleotide Sequencing
MCF-7 Cells
Research team
Cancer Genomics
Molecular & Population Genetics
Language
eng
Date accepted
2018-07-27
License start date
2018-10
Citation
Nature genetics, 2018, 50 (10), pp. 1375 - 1380

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