Abstract 5744: Characterization of sideness-related differentiated genetic alterations in stage I-IV colorectal cancer patients by using whole exome sequencing

Abstract Background: Although constituting a single organ, the right colon and left colon arise from midgut and hindgut embryonic precursors respectively. In the context of these embryonic origins, tumor laterality has been associated with differential microsatellite instability (MSI), aneuploidic karyotype, and loss of heterozygosity between the left and right colon. Differential genetic mutation profiles are not fully characterized in the context of left vs right laterality colorectal cancer (CRC). Therefore, we investigated associations between CRC anatomical site and somatic gene mutation patterns using whole exome sequencing. Methods: Whole exome sequencing data were collected from 55 FFPE samples from different stages (stage I: 11, II: 9; III: 19, IV: 16), treatment-naive CRC patients using the Personalis® tumor-only ImmunoID NeXT Platform®, which captures somatic mutations (SNVs), copy number variants (CNVs), percent MSI in the exome, oncovirus detection, etc. The R package maftools was used to identify differential rates of mutation between samples resected from the rectum, left, and right colon respectively. Maftools-derived mutated gene lists, filtered to p<0.5 and odds-ratio>1, were assessed for pathway enrichment with Enrichr. Results: APC and TP53 were the most commonly mutated genes in the entire cohort, with mutations seen in >90% (APC) and >75% (TP53) of samples respectively. Individual gene mutation frequency was not significantly different among the primary tumor locations (left colon; right colon; rectum) after Bonferroni multiple test correction, with FBXW7, APC, trending towards differential mutation between right colon tumors and left/rectal tumors. Maftools-derived mutated gene lists, filtered to p<0.5 and odds-ratio>1, were processed with Enrichr, identifying an enrichment of estrogen-related mutation events in right-sided vs rectal tumors (n=81 genes; Bioplanet 2019; q=5x10-4; WikiPathway 2021 Human; q<5x10-6). In rectal tumors compared to right side, PI3K/AKT signaling mutations were more enriched (n=106 genes; Kyoto Encyclopedia of Genes and Genomes 2021; q<4x10-6; MSigDB Hallmark 2020; q=9x10-3). Conclusion: A statistically significant increase in frequencies of estrogen pathway gene mutations on right-sided tumors, and on PI3K/AKT mutations on rectal tumors, were identified. These are consistent with prior expression-based findings indicating the association of estrogen signaling with right-sided tumors, and increased AKT expression with left-sided CRCs. The whole exome sequencing based laterality associated genetic mutation results provided clinically applicable evidence that patients suffered from left versus right CRC tumors may benefit differential treatment therapies, and further investigation is ongoing to explore the potential correlation between tumor laterality and stage. Citation Format: Danyi Wang, Lee McDaniel, Sean Boyle, Giuseppe Locatelli, Juergen Scheuenpflug, Zheng Feng. Characterization of sideness-related differentiated genetic alterations in stage I-IV colorectal cancer patients by using whole exome sequencing [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 5744.