Pan-cancer analysis of somatic mutations and epigenetic alterations in insulated neighbourhood boundaries.
Amino Acid Motifs
/ genetics
Binding Sites
/ genetics
CCCTC-Binding Factor
/ genetics
Chromosomes, Human, Pair 11
/ genetics
DNA Copy Number Variations
/ genetics
DNA Methylation
DNA Mutational Analysis
/ methods
Epigenesis, Genetic
/ genetics
Exons
/ genetics
Female
Gene Expression Regulation, Neoplastic
/ genetics
Genome, Human
/ genetics
Humans
Insulator Elements
/ genetics
Mutation Rate
Neoplasms
/ genetics
Point Mutation
Promoter Regions, Genetic
/ genetics
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
03
07
2019
accepted:
14
12
2019
entrez:
17
1
2020
pubmed:
17
1
2020
medline:
6
5
2020
Statut:
epublish
Résumé
Recent evidence shows that the disruption of constitutive insulated neighbourhoods might lead to oncogene dysregulation. We present here a systematic pan-cancer characterisation of the associations between constitutive boundaries and genome alterations in cancer. Specifically, we investigate the enrichment of somatic mutation, abnormal methylation, and copy number alteration events in the proximity of CTCF bindings overlapping with topological boundaries (junctions) in 26 cancer types. Focusing on CTCF motifs that are both in-boundary (overlapping with junctions) and active (overlapping with peaks of CTCF expression), we find a significant enrichment of somatic mutations in several cancer types. Furthermore, mutated junctions are significantly conserved across cancer types, and we also observe a positive selection of transversions rather than transitions in many cancer types. We also analyzed the mutational signature found on the different classes of CTCF motifs, finding some signatures (such as SBS26) to have a higher weight within in-boundary than off-bounday motifs. Regarding methylation, we find a significant number of over-methylated active in-boundary CTCF motifs in several cancer types; similarly to somatic-mutated junctions, they also have a significant conservation across cancer types. Finally, in several cancer types we observe that copy number alterations tend to overlap with active junctions more often than in matched normal samples. While several articles have recently reported a mutational enrichment at CTCF binding sites for specific cancer types, our analysis is pan-cancer and investigates abnormal methylation and copy number alterations in addition to somatic mutations. Our method is fully replicable and suggests several follow-up tumour-specific analyses.
Identifiants
pubmed: 31945090
doi: 10.1371/journal.pone.0227180
pii: PONE-D-19-18704
pmc: PMC6964824
doi:
Substances chimiques
CCCTC-Binding Factor
0
CTCF protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0227180Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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