Journal Article

Enrichment of colibactin-associated mutational signatures in unexplained colorectal polyposis patients

van Leerdam, Monique E., van Egmond, Demi, van Wezel, Tom, Nooij, Sam, Ruano, Dina, Morreau, Hans, Langers, Alexandra M. J., Tops, Carli M., Terlouw, Diantha, Zwittink, Romy D., Nielsen, Maartje, Boot, Arnoud, Suerink, Manon, Ducarmon, Quinten R.

2024

Overview

Background Colibactin, a genotoxin produced by polyketide synthase harboring ( pks + ) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment of pks + Escherichia coli in colorectal cancer and polyposis suggests a possible carcinogenic effect in the large intestine. Additionally, specific colibactin-associated mutational signatures; SBS88 and ID18 in the Catalogue of Somatic Mutations in Cancer database, are detected in colorectal carcinomas. Previous research showed that a recurrent APC splice variant perfectly fits SBS88. Methods In this study, we explore the presence of colibactin-associated signatures and fecal pks in an unexplained polyposis cohort. Somatic targeted Next-Generation Sequencing (NGS) was performed for 379 patients. Additionally, for a subset of 29 patients, metagenomics was performed on feces and mutational signature analyses using Whole-Genome Sequencing (WGS) on Formalin-Fixed Paraffin Embedded (FFPE) colorectal tissue blocks. Results NGS showed somatic APC variants fitting SBS88 or ID18 in at least one colorectal adenoma or carcinoma in 29% of patients. Fecal metagenomic analyses revealed enriched presence of pks genes in patients with somatic variants fitting colibactin-associated signatures compared to patients without variants fitting colibactin-associated signatures. Also, mutational signature analyses showed enrichment of SBS88 and ID18 in patients with variants fitting these signatures in NGS compared to patients without. Conclusions These findings further support colibactins ability to mutagenize colorectal mucosa and contribute to the development of colorectal adenomas and carcinomas explaining a relevant part of patients with unexplained polyposis.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adenoma / Adenomatous polyposis coli / Alternative splicing / Analysis / Bacteria / Bacterial pathogenesis / Biomedical and Life Sciences / Biomedicine / Body mass index / Cancer Research / Care and treatment / Chromosome aberrations / Colorectal adenomas / Colorectal cancer / Colorectal carcinoma / Complications and side effects / Development and progression / DNA sequencing / E coli / Escherichia coli / Escherichia coli infections / Feces / Formaldehyde / Gene mutations / Genes / Genetic aspects / Genomes / Genomics / Health aspects / Health Promotion and Disease Prevention / Hypotheses / Intestinal microbiology / Intestinal polyps / Large intestine / Lifestyles / Medical research / Medicine, Experimental / Medicine/Public Health / Metagenomics / Mutation / Next-generation sequencing / Nucleotide sequencing / Oncology / Patients / Polyketide synthase / Polyposis / Software / Surgical Oncology / Tumors / Whole genome sequencing