Abstract 1154: Multi-omic analysis classifies colorectal cancer into distinct angiogenic and immunogenic subtypes based on anatomical laterality

Abstract

Background: Colorectal cancer is a heterogeneous disease of tumors from distinct anatomical and embryological sources. According to GLOBOCAN2020, it is the second leading cause of cancer-related mortality1. Methodology: Utilising NIH-GDC2 datasets, we applied Bioinformatic algorithms to categorize LCRC and RCRC based on multi-omic variables. Mutational analysis was done using STRING v11.53. Kaplan-Meier were plotted. Transcriptome data was accessed using Bioconductor4 package TCGABiolinks5 and annotated as ‘Left’ or ‘Right’ based on tissue of origin. DE analysis was performed using DESeq6. DEGs were analyzed using Enrichr7 for signaling pathways. Further, differential methylation analysis was performed. Results: Tumors from left and right sides represent early Stage IIA non-metastatic cancers largely. Mutational analysis showed dissimilar genes in left vs right-sided tumors. CSMD1, CDH23, PCDH15, DSCAM, CDH9, and NRXN1 formed unique hubs within LCRC network while FLNC, CACNA1H, KMT2B, KMT2D, FAT4 and BRAF formed hubs in RCRC network. LCRC-specific genes were cadherins and EMT based, while RCRC-specific genes were related to lymphocytic invasion and epigenetic markers. TTN (p-value=4.61e-2) and ABCA13 (p-value=4.78e-2) significantly influenced OS in LCRC while SOX11 (p-value=4.12e-2) influenced OS in RCRC. For transcriptomic analysis, we obtained 766 DE genes at p-adjusted value <= 0.01, |log2 FC| > 1. Enrichr KEGG pathway analysis highlighted neuroactive ligand-receptor interaction (OR=3.11) and complement-coagulation cascade (OR=6.07) activity in LCRC. Platelet interaction with cancer cells have been demonstrated8 to have therapeutic potential in CRCs. NK cell mediated cytotoxicity (OR=4.33) and antigen processing-presentation (OR=6.95) were enriched in RCRC. Mean methylation analysis showed higher values in RCRC than LCRC (p-value=1.5e-05). Differential methylation gave 998 hypo- and 45 hyper-methylated genes in RCRC and LCRC respectively. RCRC evidently has an underlying hypermethylated biology when compared to LCRC. RCRCs are dependent on immune-regulated biology explaining rationale of immunotherapy. Right colon develops from midgut and is supplied by SMA. It can be hypothesized that a vast lymphatic drainage system carrying increased T-cells may play a role in creating dissimilarity. On the other hand, angiogenic factors and coagulation cascade rule left colon. This could be the reason for early metastatic potential in LCRCs. Our study unambiguously differentiates LCRC from RCRC by correlating anatomical, physiological, and multi-omic variables. Citation Format: Anu R I, Aastha Vatsyayan, Ambily Sivadas, Dileep Damodaran, Kurt van der Speeten. Multi-omic analysis classifies colorectal cancer into distinct angiogenic and immunogenic subtypes based on anatomical laterality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1154.