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DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation

Published on Jan 14, 2020in iScience
路 DOI :10.1016/j.isci.2020.100838
Douglas J. MacKenzie2
Estimated H-index: 2
(Glas.: University of Glasgow),
Neil A. Robertson7
Estimated H-index: 7
(Glas.: University of Glasgow)
+ 8 AuthorsPeter D. Adams43
Estimated H-index: 43
(Glas.: University of Glasgow)
Abstract
Summary Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG Island Methylator (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by in silico, in vitro and in vivo approaches. We conclude that while both BRAFV600E and DNMT3B both harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumour promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.
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#1Toshikazu Ushijima (Epigenomics AG)H-Index: 57
#2Hiromu Suzuki (Sapporo Medical University)H-Index: 56
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#1Yong Tao (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 16
#2Byunghak Kang (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 3
Last. Hariharan Easwaran (JHUSOM: Johns Hopkins University School of Medicine)H-Index: 8
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Summary Promoter CpG islands are typically unmethylated in normal cells, but in cancer a proportion are subject to hypermethylation. Using methylome sequencing we identified CpG islands that display partial methylation encroachment across the 5鈥 or 3鈥 CpG island borders. CpG island methylation encroachment is widespread in prostate and breast cancer and commonly associates with gene suppression. We show that the pattern of H3K4me1 at CpG island borders in normal cells predicts the different mode...
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#1Domhnall McHugh (Imperial College London)H-Index: 1
#2Jes煤s Gil (Imperial College London)H-Index: 46
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#1Rona Yaeger (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 20
#2Walid K. Chatila (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 22
Last. Nikolaus Schultz (MSK: Memorial Sloan Kettering Cancer Center)H-Index: 51
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Summary Metastatic colorectal cancers (mCRCs) are clinically heterogeneous, but the genomic basis of this variability remains poorly understood. We performed prospective targeted sequencing of 1,134 CRCs. We identified splice alterations in intronic regions of APC and large in-frame deletions in CTNNB1 , increasing oncogenic WNT pathway alterations to 96% of CRCs. Right-sided primary site in microsatellite stable mCRC was associated with shorter survival, older age at diagnosis, increased mutati...
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#2Louis Vermeulen (UvA: University of Amsterdam)H-Index: 36
Last. Josep Tabernero (Autonomous University of Barcelona)H-Index: 84
view all 6 authors...
In this Review, Dienstmann et al. analyse the complex nature of colorectal cancer and the different subtypes in which this disease can be classified, advocating for a 'multi-molecular' perspective for the development of therapies to treat it.
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#1Marios Giannakis (Broad Institute)H-Index: 21
#2Xinmeng Jasmine Mu (Broad Institute)H-Index: 25
Last. Levi A. Garraway (Broad Institute)H-Index: 100
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#2Lloyd Hutchinson (UMMS: University of Massachusetts Medical School)H-Index: 23
Last. Michael R. Green (UMMS: University of Massachusetts Medical School)H-Index: 129
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