Journal Article

DKFZ-2021-02569

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Divergent mutational processes distinguish hypoxic and normoxic tumours.

Bhandari, V. ; Li, C. H. ; Bristow, R. G. ; Boutros, P. C. ; PCAWGConsortiumExtern*

2020
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-019-14052-x

Abstract: Many primary tumours have low levels of molecular oxygen (hypoxia), and hypoxic tumours respond poorly to therapy. Pan-cancer molecular hallmarks of tumour hypoxia remain poorly understood, with limited comprehension of its associations with specific mutational processes, non-coding driver genes and evolutionary features. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancers across 38 tumour types, we quantify hypoxia in 1188 tumours spanning 27 cancer types. Elevated hypoxia associates with increased mutational load across cancer types, irrespective of underlying mutational class. The proportion of mutations attributed to several mutational signatures of unknown aetiology directly associates with the level of hypoxia, suggesting underlying mutational processes for these signatures. At the gene level, driver mutations in TP53, MYC and PTEN are enriched in hypoxic tumours, and mutations in PTEN interact with hypoxia to direct tumour evolutionary trajectories. Overall, hypoxia plays a critical role in shaping the genomic and evolutionary landscapes of cancer.

Keyword(s): Cell Hypoxia: genetics (MeSH) ; Genes, myc (MeSH) ; Genome, Human (MeSH) ; Genomic Structural Variation (MeSH) ; Humans (MeSH) ; Mutation (MeSH) ; Neoplasms: genetics (MeSH) ; Neoplasms: pathology (MeSH) ; PTEN Phosphohydrolase: genetics (MeSH) ; Polymorphism, Single Nucleotide (MeSH) ; Tumor Hypoxia: genetics (MeSH) ; Tumor Microenvironment: genetics (MeSH) ; Tumor Suppressor Protein p53: genetics (MeSH) ; Whole Genome Sequencing (MeSH) ; TP53 protein, human ; Tumor Suppressor Protein p53 ; PTEN Phosphohydrolase ; PTEN protein, human

Note: siehe Correction: DKFZ Autoren affiliiert im PCAWG Consortium:https://inrepo02.dkfz.de/record/212440 /https://doi.org/10.1038/s41467-022-32339-4

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Contributing Institute(s):

1. Theoretische Bioinformatik (B080)
2. Bioinformatik und Omics Data Analytics (B240)
3. Epigenomik (B370)
4. Angewandte Bioinformatik (B330)
5. DKTK HD zentral (HD01)
6. B060 Molekulare Genetik (B060)
7. Pädiatrische Gliomforschung (B360)
8. DKTK Koordinierungsstelle Berlin (BE01)
9. B062 Pädiatrische Neuroonkologie (B062)
10. B066 Chromatin-Netzwerke (B066)
11. B063 Krebsgenomforschung (B063)
12. Hochdurchsatz-Sequenzierung (W190)
13. B260 Bioinformatik der Genomik und Systemgenetik (B260)
14. Core Facility Omics IT (W610)
15. B087 Neuroblastom Genomik (B087)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2020

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