Characterization of colibactin-associated mutational signature in an Asian oral squamous cell carcinoma and in other mucosal tumor types

Abstract

Mutational signatures can reveal the history of mutagenic processes that cells were exposed to before and during tumorigenesis. We expect that as-yet-undiscovered mutational processes will shed further light on mutagenesis leading to carcinogenesis. With this in mind, we analyzed the mutational spectra of 36 Asian oral squamous cell carcinomas. The mutational spectra of two samples from patients who presented with oral bacterial infections showed novel mutational signatures. One of these novel signatures, SBS_AnT, is characterized by a preponderance of thymine mutations, strong transcriptional strand bias, and enrichment for adenines in the 4 bp 5′ of mutation sites. The mutational signature described in this manuscript was shown to be caused by colibactin, a bacterial mutagen produced by E. coli carrying the pks-island. Examination of publicly available sequencing data revealed SBS_AnT in 25 tumors from several mucosal tissue types, expanding the list of tissues in which this mutational signature is observed.

Recurrent APC Splice Variant c.835-8A>G in Patients With Unexplained Colorectal Polyposis Fulfilling the Colibactin Mutational Signature

“…Recently, a mutational signature caused by pksþ Escherichia coli was identified. 2,3 This signature is characterized by single base substitutions T>N mostly in ATN and TTT context with strong enrichment of adenines 3 and 4 base pairs 5 0 of the mutation site and a strong transcriptional strand bias. 3 Interestingly, the c.835-8A>G variant has a sequence context of TTAATTTTT (Figure 1A), where the underlined adenine is substituted by a guanine.…”

“…2,3 This signature is characterized by single base substitutions T>N mostly in ATN and TTT context with strong enrichment of adenines 3 and 4 base pairs 5 0 of the mutation site and a strong transcriptional strand bias. 3 Interestingly, the c.835-8A>G variant has a sequence context of TTAATTTTT (Figure 1A), where the underlined adenine is substituted by a guanine. Transformed in a T>N orientation (Figure 1B), the context perfectly fulfills the mutational signature caused by pksþ E coli with the hexanucleotide AAAATT as predominant sequencing context (Figure 1C).…”

“…Furthermore, fulfilling the signature means that the c.835-8A>G variant is suggested to arise from adducts on the untranscribed strand and is therefore not removed by transcription-coupled nucleotide excision repair. 3 Of the other recurrent variants, 7 fulfill the pksþ E coli mutational signature (Supplementary Table 2). Remarkably, in 13 patients, 50% (up to 100%) of lesions carried an APC variant fulfilling the pksþ E coli mutational signature (Supplementary Table 1).…”

“…gastro.2020.06.055. 3 For the 4 most commonly affected hexanucleotides, a breakdown of the alternative alleles is shown. AAAATT is most likely to be affected by this mutational signature, and the most common alternative allele is C.…”

Mutational signatures associated with exposure to carcinogenic microplastic compounds bisphenol A and styrene oxide

“…We also estimated frequency of mutations at 78 DBS contexts ( 34 ) (the concurrent modification of two consecutive nucleotide bases; available at https://cancer.sanger.ac.uk/cosmic/signatures/DBS ) using mut.to.sigs.inputDBS function of deconstructSigs. We further estimated frequency of small InDels at 83 InDels contexts ( 34 ) (usually 1–50bp; available at https://cancer.sanger.ac.uk/cosmic/signatures/ID ) using ICAMS packages ( 36 ) ( https://github.com/steverozen/ICAMS ) for these samples. Published SBS mutational signatures were downloaded from the COSMIC database (COSMIC v2) ( 34 ), DBS and InDels mutational signatures were downloaded from the Pan-cancer Analysis of Whole Genomes (COSMIC v2) ( 37 ).…”