학술논문
Enrichment of colibactin-associated mutational signatures in unexplained colorectal polyposis patients.
Document Type
Academic Journal
Author
Terlouw D; Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands.; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.; Boot A; Department of Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.; Ducarmon QR; Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.; Nooij S; Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.; Suerink M; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.; van Leerdam ME; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.; van Egmond D; Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands.; Tops CM; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.; Zwittink RD; Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands.; Ruano D; Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands.; Langers AMJ; Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.; Nielsen M; Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.; van Wezel T; Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands.; Morreau H; Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333 ZA, The Netherlands. j.morreau@lumc.nl.
Source
Publisher: BioMed Central Country of Publication: England NLM ID: 100967800 Publication Model: Electronic Cited Medium: Internet ISSN: 1471-2407 (Electronic) Linking ISSN: 14712407 NLM ISO Abbreviation: BMC Cancer Subsets: MEDLINE
Subject
Language
English
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.
(© 2024. The Author(s).)
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.
(© 2024. The Author(s).)