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Medientyp:
E-Artikel
Titel:
Association of mutation signature effectuating processes with mutation hotspots in driver genes and non-coding regions
Beteiligte:
Wong, John K. L.;
Aichmüller, Christian;
Schulze, Markus;
Hlevnjak, Mario;
Elgaafary, Shaymaa;
Lichter, Peter;
Zapatka, Marc
Erschienen:
Springer Science and Business Media LLC, 2022
Erschienen in:Nature Communications
Sprache:
Englisch
DOI:
10.1038/s41467-021-27792-6
ISSN:
2041-1723
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Cancer driving mutations are difficult to identify especially in the non-coding part of the genome. Here, we present sigDriver, an algorithm dedicated to call driver mutations. Using 3813 whole-genome sequenced tumors from <jats:italic>International Cancer Genome Consortium</jats:italic>, <jats:italic>The Cancer Genome Atlas Program</jats:italic>, and a childhood pan-cancer cohort, we employ mutational signatures based on single-base substitution in the context of tri- and penta-nucleotide motifs for hotspot discovery. Knowledge-based annotations on mutational hotspots reveal enrichment in coding regions and regulatory elements for 6 mutational signatures, including APOBEC and somatic hypermutation signatures. APOBEC activity is associated with 32 hotspots of which 11 are known and 11 are putative regulatory drivers. Somatic single nucleotide variants clusters detected at hypermutation-associated hotspots are distinct from translocation or gene amplifications. Patients carrying APOBEC induced <jats:italic>PIK3CA</jats:italic> driver mutations show lower occurrence of signature SBS39. In summary, sigDriver uncovers mutational processes associated with known and putative tumor drivers and hotspots particularly in the non-coding regions of the genome.</jats:p>