Riley Cox

Abstract Incidence rates of colorectal cancer vary geographically and have changed over time 1 . Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries 2–5 . The reasons for this increase are unknown. Here we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite-unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown aetiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin 6,7 , had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals who were diagnosed before 40 years of age than in those over 70 years of age, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 being responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that mutagenic exposure to colibactin-producing bacteria in early life may contribute to the increasing incidence of early-onset colorectal cancer.

Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites. Genomic, exposure, and clinical data will be publicly available through the International Cancer Genome Consortium Accelerating Research in Genomic Oncology platform. The Mutographs sample and metadata biorepository constitutes a legacy resource for new projects and collaborations aiming to increase our current research efforts in cancer genomic epidemiology globally.

ABSTRACT Colorectal cancer incidence rates vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries. The reasons for this increase are unknown. Here, we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown etiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

Abstract Background: Colorectal cancers (CRC) have an important impact on both incidence and mortality worldwide, with varying rates in different parts of the world. Despite an overall decrease in incidence in the past years, an alarming increase in early onset colorectal cancer (CRC in patients under 50 years of age) rates has been observed. As part of the Cancer Research UK Grand Challenge Mutographs project, we aim to better understand the underlying mutagenic causes contributing to the differences in CRC incidence rates through mutational signatures. Methods: We collected epidemiological data and performed whole genome sequencing and mutational signature analysis on 981 CRC tumor samples from 11 countries with varying incidence rates, including intermediate incidence regions (Iran, Colombia, Thailand, and Brazil) and higher incidence regions (Argentina, Russia, Canada, Poland, Czechia, Serbia, and Japan). Results: The average mutational profiles were similar across the countries. Mutational signatures associated with DNA repair deficiencies, including POLE and POLD1 associated signatures (SBS10a/b/c/d and SBS28), MUTYH (SBS36), NTHL1 (SBS30), homologous recombination deficiency (SBS3), and a plethora of microsatellite instability (MSI) signatures, were found in 177 cancers (18% of all samples) and at comparable levels across all countries. Multiple signatures with known etiologies were found in 802 DNA repair proficient colorectal cancers including clock-like (SBS1 and SBS5), reactive oxygen species (SBS18), APOBEC (SBS2 and SBS13), and the microbiome-product colibactin (SBS88) signatures. The colibactin signature SBS88 was observed in 14% of samples overall, being more prevalent in distal and rectum tumors. SBS88 was significantly enriched in younger patients (33% <40y, 23% 40-49y, 20% 50-59y,10% 60-69y, 10% ≥70y; p-value = 0.0001). Tumors from early onset patients also showed higher prevalence of another mutational signature with unknown etiology (19% <40y, 16% 40-49y, 13% 50-59y, 6% 60-69y, 7% ≥70y, p-value = 0.005). Conclusions: These results indicate a potential association between SBS88 with early onset CRC, suggesting that the recent increase in incidence may be at least partially explained by the genotoxic compound colibactin, and associated bacteria. Citation Format: Wellington dos Santos, Marcos Diaz-Gay, Sarah Moody, Sergey Senkin, Behnoush Abedi-Ardekani, Mariya Kazachkova, Stephen Fitzgerald, Saamin Cheema, Valerie Gaborieau, Jingwei Wang, Christine Carreira, Thomas Cattiaux, Priscilia Chopard, Calli Latimer, David Zaridze, Riley Cox, Reza Malekzadeh, Miodrag Ognjanovic, Suleeporn Sangrajrang, Maria P. Curado, Rui M. Reis, Ivana Holcatova, Carlos Vaccaro, Beata Swiatkowska, Jolanta Lissowska, Carolina Wiesner, Tatsuhiro Shibata, Surasak Sangkhathat, Patricia Ashton-Prolla, Laura Humphreys, Sandra Perdomo, Ana C. de Caravalho, Mike Stratton, Paul Brennan, Ludmil Alexandrov. Mutational signatures in colorectal cancer from 11 countries reveal new insights in early-onset colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB134.

Abstract The Ontario Tumour Bank (OTB) is a core research resource at the Ontario Institute for Cancer Research, a collaborative research institute that conducts and enables research to find cancer earlier and treat it more effectively. With 20+ years of expertise in biobanking, OTB has collected 150,000+ samples and 15,000+ whole slide images (WSIs) from 22,500+ participants across 30+ solid tumor sites. Each oncology case is comprehensively annotated with diagnostic, treatment and health data for up to 5 years. OTB has a strong record of supporting research, with acknowledgements in 200+ publications and 70,000+ citations. Recently, OTB has experienced an increased demand from commercial research clients. OTB’s samples and data can be used for many commercial applications, including fresh tumor tissue for rapid drug screening; frozen tumor and normal adjacent tissue for metabolomics; formalin-fixed paraffin-embedded tumor tissue for diagnostic assay development; plasma for predictive blood tests for cancer detection and monitoring; and WSIs combined with longitudinal health record data for prognostic AI model development. Academic biobanks such as OTB have several challenges when working with commercial research clients. These include ensuring its resources are visible and accessible to the commercial research community, as well as obtaining appropriate participant consent, ethics and contractual approvals. OTB has mitigated these challenges by asking participants to agree to a broad informed consent that includes use of their samples and data in commercial research and creating a researcher-focused website (ontariotumourbank.ca) that allows clients to submit inquiries and start the sample and data request process online. Each request is received by OTB’s dedicated senior client coordinator, who is the central point-of-contact for each client and facilitates each project from start to finish. To meet evolving research needs, commercial clients are provided access is to OTB’s deep “research ready” inventory as well as custom fresh tumor and blood collections shipped overnight immediately after collection. The number and proportion of projects, samples and data provided to commercial clients - including venture capital-supported biotechnology startups in Canada, the US and globally - has steadily increased over the past 5 years and now represents 1/3 of OTB’s business. By streamlining the request process for commercial clients, OTB has demonstrated its ability to meet the unmet demands of this sector, including emerging predictive AI model development in research and medicine. Supporting commercial research projects ensures that access to OTB’s deep inventory of quality samples and data is consistent with the wishes of our generous patient participants to support diverse academic and industry research, all while contributing to OTB’s long-term financial sustainability. Citation Format: Riley Cox, Katarina Maksimovic, Larry Phouthavongsy, Anumta Amir, Ilinca Lungu, Terry Hawrysh, Dianne Chadwick, Lincoln Stein. Ontario Tumour Bank: Accelerating commercial oncology research and development with quality samples and data [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 4812.