Dataset Information

Histone Lysine Methylation Dynamics Control EGFR DNA Copy-Number Amplification.

ABSTRACT: Acquired chromosomal DNA copy gains are a feature of many tumors; however, the mechanisms that underpin oncogene amplification are poorly understood. Recent studies have begun to uncover the importance of epigenetic states and histone lysine methyltransferases (KMT) and demethylases (KDM) in regulating transient site-specific DNA copy-number gains (TSSG). In this study, we reveal a critical interplay between a myriad of lysine methyltransferases and demethylases in modulating H3K4/9/27 methylation balance to control extrachromosomal amplification of the EGFR oncogene. This study further establishes that cellular signals (hypoxia and EGF) are able to directly promote EGFR amplification through modulation of the enzymes controlling EGFR copy gains. Moreover, we demonstrate that chemical inhibitors targeting specific KMTs and KDMs are able to promote or block extrachromosomal EGFR amplification, which identifies potential therapeutic strategies for controlling EGFR copy-number heterogeneity in cancer, and, in turn, drug response. SIGNIFICANCE: This study identifies a network of epigenetic factors and cellular signals that directly control EGFR DNA amplification. We demonstrate that chemical inhibitors targeting enzymes controlling this amplification can be used to rheostat EGFR copy number, which uncovers therapeutic opportunities for controlling EGFR DNA amplification heterogeneity and the associated drug response.This article is highlighted in the In This Issue feature, p. 161.

SUBMITTER: Clarke TL

PROVIDER: S-EPMC7271978 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Histone Lysine Methylation Dynamics Control <i>EGFR</i> DNA Copy-Number Amplification.

Clarke Thomas L TL Tang Ran R Chakraborty Damayanti D Van Rechem Capucine C Ji Fei F Mishra Sweta S Ma Anqi A Kaniskan H Ümit HÜ Jin Jian J Lawrence Michael S MS Sadreyev Ruslan I RI Whetstine Johnathan R JR

Cancer discovery 20191127 2

Acquired chromosomal DNA copy gains are a feature of many tumors; however, the mechanisms that underpin oncogene amplification are poorly understood. Recent studies have begun to uncover the importance of epigenetic states and histone lysine methyltransferases (KMT) and demethylases (KDM) in regulating transient site-specific DNA copy-number gains (TSSG). In this study, we reveal a critical interplay between a myriad of lysine methyltransferases and demethylases in modulating H3K4/9/27 methylati ...[more]

PMID: 31776131

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Project description:BACKGROUND: DNA amplifications alter gene dosage in cancer genomes by multiplying the gene copy number. Amplifications are quintessential in a considerable number of advanced cancers of various anatomical locations. The aims of this study were to classify human cancers based on their amplification patterns, explore the biological and clinical fundamentals behind their amplification-pattern based classification, and understand the characteristics in human genomic architecture that associate with amplification mechanisms. METHODS: We applied a machine learning approach to model DNA copy number amplifications using a data set of binary amplification records at chromosome sub-band resolution from 4400 cases that represent 82 cancer types. Amplification data was fused with background data: clinical, histological and biological classifications, and cytogenetic annotations. Statistical hypothesis testing was used to mine associations between the data sets. RESULTS: Probabilistic clustering of each chromosome identified 111 amplification models and divided the cancer cases into clusters. The distribution of classification terms in the amplification-model based clustering of cancer cases revealed cancer classes that were associated with specific DNA copy number amplification models. Amplification patterns - finite or bounded descriptions of the ranges of the amplifications in the chromosome - were extracted from the clustered data and expressed according to the original cytogenetic nomenclature. This was achieved by maximal frequent itemset mining using the cluster-specific data sets. The boundaries of amplification patterns were shown to be enriched with fragile sites, telomeres, centromeres, and light chromosome bands. CONCLUSIONS: Our results demonstrate that amplifications are non-random chromosomal changes and specifically selected in tumor tissue microenvironment. Furthermore, statistical evidence showed that specific chromosomal features co-localize with amplification breakpoints and link them in the amplification process.

Dataset Information

Histone Lysine Methylation Dynamics Control EGFR DNA Copy-Number Amplification.

Publications

Histone Lysine Methylation Dynamics Control <i>EGFR</i> DNA Copy-Number Amplification.

Similar Datasets

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