Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

Lindberg, Markus; Boström, Martin; Elliott, Kerryn; Larsson, Erik

doi:10.1101/640722

Cited by 10 publications

(18 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The nucleotide composition of this 11-mer subset displayed trends towards the T C S (S=C|G) center trinucleotide flanked by additional up- and downstream thymines (TTT C ST). This motif has previously been reported [21, 29, 30]. While the emergence of this motif is driven by highly mutated 11-mers with mutation rates above the mean (164 SNV/patient/Mb), we observed a different nucleotide composition in the lowly mutated contexts (WS Y T; W=A|T, Y=C|T; Suppl.…”

Section: Resultssupporting

confidence: 77%

Sequence dependencies and mutation rates of localized mutational processes in cancer

Poulsgaard

Sørensen

Juul

et al. 2021

Preprint

View full text Add to dashboard Cite

BackgroundCancer 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.ResultsWe 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.ConclusionWe summarize our findings in a catalog of localized mutational processes, their sequence preferences, and their estimated mutation rates.

show abstract

Section: Resultssupporting

confidence: 77%

Sequence dependencies and mutation rates of localized mutational processes in cancer

Poulsgaard

Sørensen

Juul

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…4 A ). Two independent maps were generated, and previously published CPD data for UVC (254 nm), generated by the same protocol, were included for comparison (29). CPDs were preferably detected at TT, TC, CT, and CC dinucleotides as expected, notably with lower TT and higher CC frequencies relative to UVC, further supporting that the 2 wavelength ranges are not physiologically equivalent (Fig.…”

Section: Resultsmentioning

confidence: 99%

Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

Lindberg

Boström

Elliott

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Mutational signatures can reveal properties of underlying mutational processes and are important when assessing signals of selection in cancer. Here, we describe the sequence characteristics of mutations induced by ultraviolet (UV) light, a major mutagen in several human cancers, in terms of extended (longer than trinucleotide) patterns as well as variability of the signature across chromatin states. Promoter regions display a distinct UV signature with reduced TCG > TTG transitions, and genome-wide mapping of UVB-induced DNA photoproducts (pyrimidine dimers) showed that this may be explained by decreased damage formation at hypomethylated promoter CpG sites. Further, an extended signature model encompassing additional information from longer contextual patterns improves modeling of UV mutations, which may enhance discrimination between drivers and passenger events. Our study presents a refined picture of the UV signature and underscores that the characteristics of a single mutational process may vary across the genome.

show abstract

“…In both keratinocyte carcinomas and melanoma skin cancers, a major risk factor is ultraviolet (UV) exposure [37][38][39] . Numerous studies have determined the effects of UV radiation on skin cancer development.…”

Section: The Role Of Cox-2 In Stem Cell-originating Cutaneous Tumor Fmentioning

confidence: 99%

“…Numerous studies have determined the effects of UV radiation on skin cancer development. UV radiation can directly act as a mutagen by causing keratinocyte and melanocyte DNA damage [37][38][39] . However, UV exposure can also act on cancer development and progression indirectly through UV-induced inflammation, which may enhance aberrant activation of tumor-prone but quiescent stem cells harboring pre-existing oncogenic mutations.…”

Section: The Role Of Cox-2 In Stem Cell-originating Cutaneous Tumor Fmentioning

confidence: 99%

New insights into the functions of Cox-2 in skin and esophageal malignancies

2020

View full text Add to dashboard Cite

Understanding the cellular and molecular mechanisms of tumor initiation and progression for each cancer type is central to making improvements in both prevention and therapy. Identifying the cancer cells of origin and the necessary and sufficient mechanisms of transformation and progression provide opportunities for improved specific clinical interventions. In the last few decades, advanced genetic manipulation techniques have facilitated rapid progress in defining the etiologies of cancers and their cells of origin. Recent studies driven by various groups have provided experimental evidence indicating the cellular origins for each type of skin and esophageal cancer and have identified underlying mechanisms that stem/progenitor cells use to initiate tumor development. Specifically, cyclooxygenase-2 (Cox-2) is associated with tumor initiation and progression in many cancer types. Recent studies provide data demonstrating the roles of Cox-2 in skin and esophageal malignancies, especially in squamous cell carcinomas (SCCs) occurring in both sites. Here, we review experimental evidence aiming to define the origins of skin and esophageal cancers and discuss how Cox-2 contributes to tumorigenesis and differentiation.

show abstract

Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

Cited by 10 publications

References 40 publications

Sequence dependencies and mutation rates of localized mutational processes in cancer

Sequence dependencies and mutation rates of localized mutational processes in cancer

Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light

New insights into the functions of Cox-2 in skin and esophageal malignancies

Contact Info

Product

Resources

About