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Mutational signatures can reveal the history of mutagenic processes that cells were exposed to prior to and during tumourigenesis. 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 striking enrichment for adenines in the 4 base pairs 5′ of mutation sites. Examination of publicly available sequencing data revealed SBS_AnT in 25 tumours from several mucosal tissue types, all of which harbour human symbionts or are adjacent to tissues that harbour symbionts. Data in a preprint released while this manuscript was in revision strongly suggest that the bacterial compound colibactin causes SBS_AnT. Footnotes * revised version, also added reference to a recent preprint describing double-strand breaks induced by colibactin, which predominantly occur in nearly the identical sequence context (AAWWTT) that we also observe for SBSs in our data

Somatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair and/or replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes contributing to the development of human cancer including a comprehensive reference set of mutational signatures in human cancer. Footnotes * https://doi.org/10.7303/syn11726601

Acrylamide, a probable human carcinogen, is ubiquitously present in the human environment, with sources including heated starchy foods, coffee and cigarette smoke. Humans are also exposed to acrylamide occupationally. Acrylamide is genotoxic, inducing gene mutations and chromosomal aberrations in various experimental settings. Covalent haemoglobin adducts were reported in acrylamide-exposed humans and DNA adducts in experimental systems. The carcinogenicity of acrylamide has been attributed to the effects of glycidamide, its reactive and mutagenic metabolite capable of inducing rodent tumors at various anatomical sites. In order to characterize the pre-mutagenic DNA lesions and global mutation spectra induced by acrylamide and glycidamide, we combined DNA-adduct and whole-exome sequencing analyses in an established exposure-clonal immortalization system based on mouse embryonic fibroblasts. Sequencing and computational analysis revealed a unique mutational signature of glycidamide, characterized by predominant T:A>A:T transversions, followed by T:A>C:G and C:G>A:T mutations exhibiting specific trinucleotide contexts and significant transcription strand bias. Computational interrogation of human cancer genome sequencing data indicated that a combination of the glycidamide signature and an experimental benzo[a]pyrene signature are nearly equivalent to the COSMIC tobacco-smoking related signature 4 in lung adenocarcinomas and squamous cell carcinomas. We found a more variable relationship between the glycidamide- and benzo[a]pyrene-signatures and COSMIC signature 4 in liver cancer, indicating more complex exposures in the liver. Our study demonstrates that the controlled experimental characterization of specific genetic damage associated with glycidamide exposure facilitates identifying corresponding patterns in cancer genome data, thereby underscoring how mutation signature laboratory experimentation contributes to the elucidation of cancer causation.

To report the incidence of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor and the safety profile of multiple doses of bevacizumab from the same vial reused for multiple patients. Case series. A private hospital in Hong Kong. A systematic retrospective review of consecutive intravitreal anti-vascular endothelial growth factor injections between 5 June 2006 and 17 December 2010 at a single institute was conducted. Patients were identified from prospectively designed audit forms, and each patient's medical record was reviewed for any documented complications. Bevacizumab 1.25 mg/0.05 mL to 2.50 mg/0.1 mL was aspirated from the designated vial, with a maximum of 10 consecutive injections being aspirated from the same vial. The opened vial was then discarded without overnight storage. Ranibizumab was aspirated from the commercially available 1 mg/0.1 mL single-use vial. A total of 1655 intravitreal anti-vascular endothelial growth factor injections into 392 eyes of 383 patients were evaluated during the study period. There were 1184 bevacizumab injections and 471 ranibizumab injections. There was one case of suspected endophthalmitis after ranibizumab injection, though culture of the vitreous tap was negative. The point prevalence of endophthalmitis was 0.06% (1/1655) for the total number of injections: 0.21% (1/471) after ranibizumab, and 0% after bevacizumab. Although many centres aliquot multiple syringes from a single vial to be kept in a refrigerator for use, the current study shows that so long as proper sterile techniques are implemented, there were no cases of endophthalmitis from using the same vial, which was reused for a maximum of 10 consecutive injections. For intravitreal injection, bevacizumab costs approximately US$50 to US$100 per dose, as opposed to US$2000 per dose for ranibizumab. Sharing multiple doses of bevacizumab from a single vial can substantially reduce the cost of treatment.