Abstract
Study of mutational signatures in cancers can reveal the history of mutagenic processes that cells were exposed to prior and during tumourigenesis. Although recent work has identified 65 distinct single nucleotide substitution signatures, we expect that as-yet-undiscovered mutational processes will be able to shed further light on mutagenesis leading to carcinogenesis. For this reason we analyzed mutational signatures in whole-exome sequencing data of 36 Asian oral squamous cell carcinomas.
The mutational spectra of most of the carcinomas could be explained by known mutational signatures, but one sample showed a novel mutational signature. Whole-genome sequencing revealed that this mutational signature was characterized by a preponderance of thymine mutations, strong transcriptional strand bias, and a striking enrichment for adenines in the 4 base pairs 5’ of mutation sites. The enrichment was strongest 3 base pairs 5’ of mutated thymines, where 93.5% of bases were adenines. We also observed deletions of single thymines inside and outside of thymine repeats with similar 5’ enrichment for adenines. Examination of publicly available whole-genome and whole-exome sequencing data of 23,829 tumours revealed this signature in 23 tumours from sites including the bile-duct, bladder, pancreas and rectum.
Although the aetiology of this mutational signature remains unknown, the transcriptional strand bias suggests adduct formation on adenines. We speculate that the signature may have been caused by duocarmycins, naturally occurring large DNA-crosslinking molecules, which were also used in the past in clinical trials. We call this novel mutational signature SBS_AnT.
Novelty and impact Here, we describe a novel mutational signature with exceptional enrichment for adenines in the 4 base pairs 5’ of mutation sites. We first observed this signature in an oral squamous cell cancer in which it dominated, and then detected it in 23 of 23,829 tumours that had publicly available data. Identification of rare mutational signatures can lead to improved understanding of carcinogenesis and carcinogenic compounds, thereby leading to improved prevention strategies.
- Abbreviations
- bp
- base pair
- indels
- insertions and deletions
- SBS
- single base substitutions
- DNS
- dinucleotide substitutions
- HNSCC
- head and neck squamous cell carcinoma
- OSCC
- oral squamous cell carcinoma
- PCAWG
- Pan-Cancer Analysis of Whole Genomes
- TC-NER
- transcription coupled nucleotide excision repair