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Sequence dependencies and mutation rates of localized mutational processes in cancer

View ORCID ProfileGustav Alexander Poulsgaard, Simon Grund Sørensen, Randi Istrup Juul, Morten Muhlig Nielsen, Jakob Skou Pedersen
doi: https://doi.org/10.1101/2021.10.27.465848
Gustav Alexander Poulsgaard
1Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
2Department of Molecular Medicine (MOMA), Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
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  • ORCID record for Gustav Alexander Poulsgaard
Simon Grund Sørensen
1Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
2Department of Molecular Medicine (MOMA), Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
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Randi Istrup Juul
1Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
2Department of Molecular Medicine (MOMA), Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
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Morten Muhlig Nielsen
1Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
2Department of Molecular Medicine (MOMA), Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
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Jakob Skou Pedersen
1Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 82, 8200, Aarhus N, Denmark
2Department of Molecular Medicine (MOMA), Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
3Bioinformatics Research Center (BiRC), Aarhus University, 8000, Aarhus C, Denmark
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  • For correspondence: jakob.skou@clin.au.dk
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Abstract

Background Cancer mutations accumulate through replication errors and DNA damage coupled with incomplete repair. Individual mutational processes often show strong sequence and regional preferences. As a result, some sequence contexts mutate at much higher rates than others. Mutational hotspots, with recurrent mutations across cancer samples, represent genomic positions with elevated mutation rates, often caused by highly localized mutational processes.

Results We analyze the mutation rates of all 11-mer genomic sequence contexts using the PCAWG set of 2,583 pan-cancer whole genomes. We further associate individual mutations and contexts to mutational signatures and estimate their relative mutation rates. 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), 7a (UV), and 72 (linked to lymphomas). In some cases, the mutation rate increases further when focusing on certain genomic regions, such as signature 62 in poised promoters, where the mutation is increased several thousand folds over the overall data set average.

Conclusion We summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 28, 2021.
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Sequence dependencies and mutation rates of localized mutational processes in cancer
Gustav Alexander Poulsgaard, Simon Grund Sørensen, Randi Istrup Juul, Morten Muhlig Nielsen, Jakob Skou Pedersen
bioRxiv 2021.10.27.465848; doi: https://doi.org/10.1101/2021.10.27.465848
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Sequence dependencies and mutation rates of localized mutational processes in cancer
Gustav Alexander Poulsgaard, Simon Grund Sørensen, Randi Istrup Juul, Morten Muhlig Nielsen, Jakob Skou Pedersen
bioRxiv 2021.10.27.465848; doi: https://doi.org/10.1101/2021.10.27.465848

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