TY - JOUR
T1 - Sequence dependencies and mutation rates of localized mutational processes in cancer
AU - Poulsgaard, Gustav Alexander
AU - Sørensen, Simon Grund
AU - Juul, Randi Istrup
AU - Nielsen, Morten Muhlig
AU - Pedersen, Jakob Skou
N1 - Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
PY - 2023/12
Y1 - 2023/12
N2 - Background: Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show nucleotide sequence and functional region preferences. As a result, some sequence contexts mutate at much higher rates than others, with additional variation found between functional regions. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes. Methods: We count the 11-mer genomic sequences across the genome, and using the PCAWG set of 2583 pan-cancer whole genomes, we associate 11-mers with mutational signatures, hotspots of single nucleotide variants, and specific genomic regions. We evaluate the mutation rates of individual and combined sets of 11-mers and derive mutational sequence motifs. Results: We show that hotspots generally identify highly mutable sequence contexts. Using these, we show that some mutational signatures are enriched in hotspot sequence contexts, corresponding to well-defined sequence preferences for the underlying localized mutational processes. This includes signature 17b (of unknown etiology) and signatures 62 (POLE deficiency), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate and sequence preference increase further when focusing on certain genomic regions, such as signature 62 in transcribed regions, where the mutation rate is increased up to 9-folds over cancer type and mutational signature average. Conclusions: We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.
AB - Background: Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show nucleotide sequence and functional region preferences. As a result, some sequence contexts mutate at much higher rates than others, with additional variation found between functional regions. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes. Methods: We count the 11-mer genomic sequences across the genome, and using the PCAWG set of 2583 pan-cancer whole genomes, we associate 11-mers with mutational signatures, hotspots of single nucleotide variants, and specific genomic regions. We evaluate the mutation rates of individual and combined sets of 11-mers and derive mutational sequence motifs. Results: We show that hotspots generally identify highly mutable sequence contexts. Using these, we show that some mutational signatures are enriched in hotspot sequence contexts, corresponding to well-defined sequence preferences for the underlying localized mutational processes. This includes signature 17b (of unknown etiology) and signatures 62 (POLE deficiency), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate and sequence preference increase further when focusing on certain genomic regions, such as signature 62 in transcribed regions, where the mutation rate is increased up to 9-folds over cancer type and mutational signature average. Conclusions: We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.
KW - Hotspots
KW - Mutation rate
KW - Mutational processes
KW - Pan-cancer
UR - http://www.scopus.com/inward/record.url?scp=85168292562&partnerID=8YFLogxK
U2 - 10.1186/s13073-023-01217-z
DO - 10.1186/s13073-023-01217-z
M3 - Journal article
C2 - 37592287
AN - SCOPUS:85168292562
SN - 1756-994X
VL - 15
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 63
ER -