Abstract IA25: The role of genetics and microbiomics in colorectal cancer among African American patients

Abstract

Abstract Colorectal cancer (CRC) is the third cause of death in the USA and genomic and microbiomic alterations play an important role in its development. Much of the underlying genomic “cancer driver” mutations and microbiomic actors in sporadic CRC are still under investigation. Here, we report the identification of distinct novel variants from CRC patients in mismatch repair (MMR) genes (MSH2, MHS3, and MSH6), and APC. We used targeted sequencing in 138 colon tissues to examine 98.8% of the targeted exons and splice junctions at a depth of sequencing that allowed for high confidence variant calling. After alignment and variant calling, we annotated the variants with information from the 1000 Genomes Project, COSMIC, Polyphen2, and PFAM domain and transcription factor motifs. Excluding synonymous SNVs, 212 deleterious variants in adenoma, 760 in advanced adenoma, and 2624 variants in tumors were detected. Novel variants (1591 and 1363) were found in MMR genes (MSH6 and MSH3) and APC gene, respectively. We also evaluated the utility of fecal bacterial marker candidates identified by our metagenomic analysis for CRC diagnosis. We identified Fusobacterium nucleatum as a major marker when comparing cancer vs. matched normal tissue and adenoma patients' stools vs. healthy subjects' stools. We also identified a novel bacterium Streptococcus sp. VT_162 with high diagnostic value in stool samples of preneoplastic patients. In vitro experiments showed that this bacterium promotes several carcinogenic pathways and downregulates apoptotic functions. This bacterium's diagnostic value was validated in an independent CRC cohort. Together our findings highlight the relevance of APC gene in CRC onset but also the potential underestimation of the MSI-H phenotype, especially the one associating with MSH3 alterations that correlate with poor prognosis. Many of the so-called “uncertain significance” novel mutations in MMR genes detected here were of a deleterious nature with potential therapeutic impact. Functional analysis of the novel gene targets is needed to confirm their roles in associated carcinogenic pathways. The role of immune markers is an important player in MMR defective tumors (MSI) as a result of neoantigen formation and in response to microbiomic alterations. These findings might facilitate noninvasive screening for CRC. Citation Format: Hassan Ashktorab, Hassan Brim. The role of genetics and microbiomics in colorectal cancer among African American patients [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA25.