Abstract LB374: The microbial landscape of colorectal cancer across 11 countries

Abstract Colorectal cancer (CRC) is the second most frequent cause of cancer-related deaths globally. CRC is influenced by the colorectal microbiome, which plays a pivotal role in inflammation, DNA damage, and production of cancer-promoting metabolites. Most prior CRC microbial studies have identified multiple microbes enriched in tumor samples, but these examinations have generally focused on CRC from a specific country and have not accounted for CRC patient’s tumor site, sex, diet, or geographical location. Further, the interconnection between somatic alterations and microbiome composition has not been comprehensively explored. Here, we examine the microbiome profiles of 963 whole-genome sequenced CRC and their matched-normal blood from 11 different countries with highly varying age-standardized incidence rate (ASR) for colorectal cancer. Matched normal blood samples exhibited a strong intra- and inter-microbial heterogeneity across the 11 countries. In contrast, while CRC tumors exhibited a higher microbial diversity when compared to their matched-normal samples, the top 10 most abundant CRC taxa were strikingly similar across all countries, suggesting a global convergence of the CRC microbiome composition. Moreover, a positive correlation was observed between the colorectal cancer ASR across 11 countries and the CRC microbial diversity (rho=0. 91, p-value: 0. 0002), suggesting that countries with high incidence rates also have high microbial diversities. After accounting for age, shipment batch, sex, and country-specific effects on the microbiome composition, we observed a core set of five microbial species enriched in CRC across all countries, which included Bacteroides fragilis, Phocaeicola Vulgatus, Faecalibacterium Prausnitzii, Fusobacterium Nucleatum, and Escherichia Coli. A strong correlation (rho=0. 84, p-value: 0. 0013) was observed between Bacteroides fragilis and a novel mutational signature characterized by A/TCGT and TTGN substitutions. No association was observed between polyketide synthase gene complex (pks) + microbe and the presence of the pks-derived colibactin mutational signatures. Furthermore, additional associations were observed between the microbiome and other mutational signatures and driver genes. Overall, this study delivers a global atlas of the microbial landscapes of CRC genomes across 11 countries and their links with genetic changes and epidemiological risk factors. Citation Format: Ammal Abbasi, Ludmil Alexandrov. The microbial landscape of colorectal cancer across 11 countries 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 (7Suppl): Abstract nr LB374.