Abstract
Abstract Objective: Colorectal cancer (CRC) is usually classified as proximal, distal and rectal cancer. clinicopathological, molecular features and risk factors do not change abruptly and variations exist even among the refined subsites, which may contribute to the failure of mechanism-targeted therapies for CRC and poor accuracy of potential CRC biomarkers. We generated a CRC metabolome map describing etiological and survival heterogeneity in cancers of different subsites of the colorectum. Design: Utilizing 372 tumor tissues with matched normal mucosa liquid chromatography-mass spectrometry was applied to examine metabolomics profiles along 7 subsites of the colorectum: cecum (n=63), ascending colon (n=44), transverse colon (n=32), descending colon (n=28), sigmoid colon (n=75), rectosigmoid colon (n=38) and rectum (n=92). Linear regression showed distribution of metabolites along the subsites. Survival heterogeneity along subsites were statistically tested by cox regression analysis. Metabolome profiles were obtained from invitro cultures of 310 human microbial species. Results: 40 and 76 significantly altered metabolites (including bile acids, lysoPCs and LysPEs) among tumors and normal mucosa showed metabolic heterogeneity existed among CRC subsites. Gradual changes in metabolites abundance with significantly linear trend from cecum to rectum: 23 metabolites in tumor, 30 metabolites in normal mucosa and 15 metabolites in both tumor and normal mucosa, revealed concentration gradient depends on the disease status. Exclusively significant alteration of metabolites only in one subsite showed the differences in cancers among the 7 subsites of colorectum. We identified the metabolites associated with survival were different and unique to each subsite. Integration of microbial metabolome with CRC metabolome revealed microbial metabolites contributed to etiological and survival heterogeneity among CRC subsites. Conclusions: Gradual changes of metabolites from cecum to rectum and the association of different metabolites with CRC risk and survival in each subsite of colorectum, revealed the differences in cancers along the colorectum and challenge the simple classification of CRC in LCC, RCC and rectum. Human microbial metabolites contributed to etiological and survival heterogeneity among CRC subsites. Citation Format: Abhishek Jain, Caroline Johnson, Domenica Berardi, Sajid Khan, Montana Morris. Colorectum metabolome map revealed etiological and survival heterogeneity in cancers of different subsites: Challenging the proximal versus distal classification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3112.
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