Dysregulated TCA Cycle Pathway in Endometrial Cancer

Yuexin Liu

Abstract


Background: Numerous questions regarding metabolism alterations in endometrial cancer remain unanswered. Methods: We used the Mann-Whitney test to identify significantly downregulated genes in Cluster II, which were then subject to Ingenuity Pathway Analysis and Gene Ontology (GO) enrichment analysis. We next compared the expression levels of several key enzymes between the CTNNB1 mutant and wide-type patients to correlate “TCA Cycle” alterations with CTNNB1 mutation status. Finally, we performed a Spearman correlation between the TCA Cycle genes and the immune checkpoint molecule to understand the relationship between TCA Cycle dysfunction and immune response. All statistical tests were two-sided. Results: A total of 603 genes were significantly downregulated in Cluster II. Pathway analysis showed that metabolic pathways were frequently dysregulated, and GO analysis demonstrated that metabolic processes were commonly retarded. In particular, TCA Cycle is the most significantly altered metabolic pathway (P = 1.45 x 10-07), with one-third of the enzymes altered. The TCA Cycle pathway activity and the expression levels of several key enzymes were significantly lower in CTNNB1 mutant patients, compared to CTNNB1 wide-type patients. In addition, the TCA Cycle pathway activity and the expression levels of pathway genes were significantly and positively correlated with PD-L1 gene expression. Conclusion: This study systematically characterizes a subset of endometrioid endometrial cancer patients with dysregulated TCA Cycle pathway, which may contribute to immune resistance in endometrial cancer.


Keywords


TCA cycle; metabolism; CTNNB1 mutation; immune response; endometrial cancer

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DOI: http://dx.doi.org/10.30564/amor.v4i6.197

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