Abstract Background: Colorectal adenomatous polyposis is usually linked to genetic predisposition, and affected patients should receive genetic counselling and germline testing. In APC-associated polyposis, the absence of a suggestive family history does not exclude the diagnosis, given the frequency of de novo mutations. APC mutations may arise postzygotically, resulting in a somatic mosaicism in a significant fraction of patients who show no germline alterations. However, a substantial proportion of patients remain genetically unexplained, suggesting that additional mechanisms, possibly environmental or microbial, may contribute to disease onset and progression. Growing evidence suggests that gut microbiota (especially pks+ Escherichia coli that produce the colibactin) may induce characteristic DNA mutations thus contributing to the disease. Methods: In this study, 125 patients with unexplained colorectal adenomatous polyposis were included. Next-generation sequencing was performed on 337 polyps and 173 healthy tissues. Somatic mosaicism was diagnosed when a same APC pathogenic mutation was identified in ≥ 3 neoplastic lesions or in healthy biopsies and in ≥ 1 colonic lesion (n=60 patients). Colibactin-associated APC variants were identified and the presence of pks+ bacteria was explored by qPCR. Finally, the clonal architecture of each lesion was inferred by classifying all mutations as clonal or subclonal. Results: APC somatic mosaicism was identified in 22 patients (36.7% of assessed cases). Most mosaic variants were not detectable in blood, except in two patients who showed low-level germline mosaicism. Overall, 94.4% of neoplastic lesions carried a somatic APC variant; those without APC mutations often harbored alterations in other driver genes such as KRAS, BRAF, CTNNB1 or RNF43. Several APC mutations showed patterns characteristic of exposure to colibactin, produced by pks+ bacteria, including the recurrent splice-site mutation c.835-8AG. Nearly 19% of lesions displayed mutations fitting the colibactin-associated signature. PCR testing for pks+ bacteria was positive in 22% of samples, but there was no concordance between pks+ PCR positivity and colibactin-related mutations, suggesting that exposure may be past or transient. The clonal analyses indicated that mosaic and colibactin-associated APC mutations are early, clonal events detected in multiple polyps. A rare case of transmission of a mosaic APC variant to offspring confirmed the early acquisition and possible involvement of germline cells. In contrast, mutations in other driver genes tend to appear later, as subclonal alterations. Conclusion: Overall, the findings suggest that somatic APC mosaicism explains one third of unexplained colorectal adenomatous polyposis. Moreover, early-life exposure to colibactin-producing bacteria may also contribute to disease initiation and progression in some patients. Citation Format: Keltouma Driouch, Zakia Tariq, Antoine Dardenne, Marion Dhooge, Jeanne Netter-Coti, Marine Le Mentec, Solenne Farelly, Marie-Clemence Gorenstein, Ivan Bièche, Albain Chansavang, Eric pasmant, Chrystelle Colas, Olfa Trabelsi-Grati, Bruno Buecher. APC mosaicism and colibactin-associated signature as key factors in unexplained colorectal polyposis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4070.
Driouch et al. (Fri,) studied this question.