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Open Access 01-12-2024 | Research

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

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

Published in: BMC Cancer | Issue 1/2024

Abstract

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.

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Title: Enrichment of colibactin-associated mutational signatures in unexplained colorectal polyposis patients
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
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-024-11849-y

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