Extrachromosomal driver mutations in glioblastoma and low-grade glioma

Nikolaev, Sergey I.; Santoni, Federico; Garieri, Marco; Makrythanasis, Periklis; Falconnet, Emilie; Guipponi, Michel; Vannier, Anne; Radovanović, Ivan; Béna, Frédérique; Forestier, F; Schaller, Karl; Dutoit, Valérie; Clément-Schatlo, Virginie; Dietrich, Pierre‐Yves; Antonarakis, Stylianos E.

doi:10.1038/ncomms6690

Cited by 77 publications

(96 citation statements)

References 53 publications

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“…As reported before 27 , cells were digested with Trypsin-EDTA 0.05% (Gibco) for 10 min at 37 °C. The cells were mixed with 10% FCS-PBS, and a single-cell suspension was obtained using a 40-µm cell strainer 30 . After centrifugation, cells were resuspended in 10% FCS-PBS again and fixed in 1% paraformaldehyde (PFA) for 10 min at room temperature and reaction quenched with 2.5M glycine (Merck) on ice and centrifuged at 400g for 8min.…”

Section: Chip-seqmentioning

confidence: 99%

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Helmsauer

Валиева

Ali

et al. 2019

Preprint

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MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA. The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyzed the MYCN amplicon structure and its chromatin landscape. This revealed two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplified a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons was characterized by high structural complexity, lacked key local enhancers, and instead contained distal chromosomal fragments, which harbored CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.

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Section: Chip-seqmentioning

confidence: 99%

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Helmsauer

Валиева

Ali

et al. 2019

Preprint

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“…Further analysis of focal amplifications, defined as regions at CN ≥ 4 and smaller than 6Mb 46 , in 1,268 tumors and 162 normal tissue samples with RNA-seq data available reveals that 6,310 focal amplifications encompassing oncogenes (11.1%; 20.5% when including low-confidence calls) localize to chromothripsis regions, and often leading to increased expression (Supplementary Table 2). These include well-known cancer genes, such as CCND1 (25 tumors), CDK4 (25), MDM2 (23), SETDB1 (23), ERBB3 (11), ERBB2 (11), MYC (10), and MYCN (5).…”

Section: Oncogene Amplification In Chromothripsis Regionsmentioning

confidence: 99%

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Cortés-Ciriano

Lee

et al. 2018

Preprint

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SummaryChromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.

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“…TSG regions are more likely to harbor mutations that may impact protein stability through changes in hydrophobicity or volume. Potential explanations for these differences are that there are more ways to lose the function of a protein than to gain function (43). Loss-of-function tumor suppressor mutations can occur at many residue positions and involve many types of amino acid residue substitutions, while oncogene mutations will occur at a few functionally important positions and involve fewer substitution types.…”

Section: Discussionmentioning

confidence: 99%

“…In these tumor types, EGFR mutation patterns is atypical, because EGFR amplification is an early event. This amplification has been linked to increased mutation load in EGFR itself, including in aberrant extrachromosomal copies of EGFR (43). Fig S2 indicates the locations of these misclassified regions on the PCA plot.…”

Section: Discussionmentioning

confidence: 99%

Exome-Scale Discovery of Hotspot Mutation Regions in Human Cancer Using 3D Protein Structure

et al. 2016

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The impact of somatic missense mutation on cancer etiology and progression is often difficult to interpret. One common approach for assessing the contribution of missense mutations in carcinogenesis is to identify genes mutated with statistically nonrandom frequencies. Even given the large number of sequenced cancer samples currently available, this approach remains underpowered to detect drivers, particularly in less studied cancer types. Alternative statistical and bioinformatic approaches are needed. One approach to increase power is to focus on localized regions of increased missense mutation density or hotspot regions, rather than a whole gene or protein domain. Detecting missense mutation hotspot regions in three dimensional protein structure may also be beneficial, because linear sequence alone does not fully describe the biologically relevant organization of codons. Here, we present a novel and statistically rigorous algorithm for detecting missense mutation hotspot regions in 3D protein structures. We analyze ~3×105 mutations from The Cancer Genome Atlas (TCGA) and identify 216 tumor-type-specific hotspot regions. In addition to experimentally determined protein structures we consider high-quality structural models, which increases genomic coverage from ~5,000 to more than 15,000 genes. We provide new evidence that 3D mutation analysis has unique advantages. It enables discovery of hotspot regions in many more genes than previously shown and increases sensitivity to hotspot regions in tumor suppressor genes. While hotspot regions have long been known to exist in both tumor suppressor genes and oncogenes, we provide the first report that they have different characteristic properties in the two types of driver genes. We show how cancer researchers can use our results to link 3D protein structure and the biological functions of missense mutations in cancer, and to generate testable hypotheses about driver mechanisms. Our results are included in a new interactive website for visualizing protein structures with TCGA mutations and associated hotspot regions. Users can submit new sequence data, facilitating the visualization of mutations in a biologically relevant context.

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Extrachromosomal driver mutations in glioblastoma and low-grade glioma

Cited by 77 publications

References 53 publications

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

Exome-Scale Discovery of Hotspot Mutation Regions in Human Cancer Using 3D Protein Structure

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