Abstract 5901: Microbiome and genomic profiling in rectal adenocarcinoma

Abstract Introduction: Recent studies have identified bacteria associated with colorectal cancer (CRC), with some data supporting causality in preclinical CRC models. We examined the gut microbiome composition and tumor genomic profiles in a diverse cohort of rectal cancer patients. Methods: Twenty-two patients with newly-diagnosed, Stage II-IV rectal cancer without pathogenic germline mutations (mismatch repair genes, MUTYH) were included in the study. Gut microbiome profiling was performed on genomic DNA extracted from collected fecal samples (16S rRNA sequencing, V4 region). Tumor specimens were tested for somatic and germline mutations using the Tempus xT 648-gene panel and whole transcriptome RNA sequencing, providing information on tumor mutation burden (TMB), pathogenic KRAS mutation status and consensus molecular subtype (CMS). We then assessed differential abundance of microbial taxa (using ANCOM-BC) between the following groups: high vs low TMB (dichotomized at median, 3.7 mut/MB), presence versus absence of pathogenic KRAS mutation, and CMS subtype. Results: The median age of study subjects was 49 years (range 37-78). Racial/ethnic breakdown was as follows: 2 non-Hispanic Asian, 4 non-Hispanic Black, 5 non-Hispanic White, and 11 White Hispanic. Twelve tumors carried a pathogenic KRAS variant and the median TMB was 3.7 m/MB (range 0.5-8.9 m/MB). Among 20 tumors that underwent whole transcriptome RNA sequencing, 1 was categorized as CMS1, 8 CMS2, 3 CMS3, 7 CMS4, and 2 CMS undetermined. There were no statistically significant differences in gut bacteria taxa abundance by KRAS mutation status or among CMS subtypes. The group with greater than median TMB, however, had statistically significant enrichment of Pepostreptococcus stomatis (18.4 fold increase, p=0.039 after Benjamini-Hotchberg adjustment with FDR = 0.05). Conclusions: In this pilot study, we found that CRC patients with higher TMB had an enrichment of Peptostreptococcus stomatis, a bacteria associated with colonic dysplasia in mouse models and enriched in CRC patients as compared to healthy controls. (PMID 28823860, 35292756) Higher TMB is a predictive biomarker for response to immunotherapy across cancer types including CRC. Since the gut microbiome is potentially modifiable, further research is needed to better elucidate the connection between microbiome and CRC carcinogenesis including specific mutation profiles, which could pave the way for microbiome-related risk reduction or therapeutic strategies in CRC. Citation Format: David Hein, Laura Coughlin, Nicole Poulides, Andrew Koh, Nina Sanford. Microbiome and genomic profiling in rectal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5901.