Abstract
The interplay between the sex-specific differences in tumor metabolome and colorectal cancer (CRC) prognosis has never been studied and represents an opportunity to improve patient outcomes. This study examines the link between tumor metabolome and prognosis by sex for CRC patients. Using untargeted metabolomics analysis, abundances of 91 metabolites were obtained from primary tumor tissues from 197 patients (N = 95 females, N = 102 males) after surgical colectomy for stage I-III CRC. Cox Proportional hazard (PH) regression models estimated the associations between tumor metabolome and 5-year overall survival (OS) and recurrence-free survival (RFS), and their interactions with sex. Eleven metabolites had significant sex differences in their associations with 5-year OS, and five metabolites for 5-year RFS. The metabolites asparagine and serine had sex interactions for both OS and RFS. Furthermore, in the asparagine synthetase (ASNS)-catalyzed asparagine synthesis pathway, asparagine was associated with substantially poorer OS (HR (95% CI): 6.39 (1.78–22.91)) and RFS (HR (95% CI): 4.36 (1.39–13.68)) for female patients only. Similar prognostic disadvantages in females were seen in lysophospholipid and polyamine synthesis. Unique metabolite profiles indicated that increased asparagine synthesis was associated with poorer prognosis for females only, providing insight into precision medicine for CRC treatment stratified by sex.
Highlights
According to the U.S Centers for Disease Control and Detection (CDC), colorectal cancer (CRC) was the third leading cause of cancer-related deaths in the United States in 2021 [1]
Other critical metabolites in polyamine synthesis did not have significant sex interactions (Table S13). This is the first study to show that sex-specific differences in the CRC tumor metabolome are linked to prognosis based on data from one of the largest metabolomics study cohorts
By applying state-of-the-art mass spectrometry to fresh frozen specimens acquired operatively in a large colorectal biorepository, we show that females have a distinct metabolite profile, underscored by asparagine metabolism, which correlates with prognosis after surgical colectomy
Summary
According to the U.S Centers for Disease Control and Detection (CDC), colorectal cancer (CRC) was the third leading cause of cancer-related deaths in the United States in 2021 [1]. Prognosis is partly dependent on stage at presentation according to the TNM classification system based on the American Joint Committee on Cancer (AJCC) [2] and the Union for International Cancer Control (UICC) [3]. The application of biomarkers in a clinical context has the potential to improve prognosis based on gene mutations [8,9], microRNAs [10], and DNA methylation [11,12]. CRC metabolomic studies have shown the correlation of certain metabolite profiles to cancer survival and recurrence using biological samples of urine and tissue [14]. Some plasma metabolites are associated with recurrence in stage II and III patients [15], showing the potential value of metabolomics in finding prognostic biomarkers of CRC
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