Enrichment of Colibactin-associated Mutational Signatures in Unexplained Colorectal Polyposis Patients

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2024 Jan 18

PMID 38238650

Authors

Diantha Terlouw

Arnoud Boot

Quinten R Ducarmon

Sam Nooij

Manon Suerink

Monique E van Leerdam

Demi van Egmond

Carli M Tops

Romy D Zwittink

Dina Ruano

Alexandra M J Langers

Maartje Nielsen

Tom van Wezel

Hans Morreau

Affiliations

Soon will be listed here.

Abstract

Background: Colibactin, a genotoxin produced by polyketide synthase harboring (pks) bacteria, induces double-strand breaks and chromosome aberrations. Consequently, enrichment of pksEscherichia 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.

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