Sex-based differences in the transcriptomic metabolic profiling in young onset colorectal cancer (YOCRC).
Authors: Vadehra Deepak , Rosario Spencer , Wang Jianmin , Zhang Yali , Isenhart Emily , Kolesar Jill , Ibrahimi Sami , Singer Eric A. , Spakowicz Daniel , Owen Dwight Hall , Churchman Michelle L. , Mukherjee Sarbajit 
Published: January 2024

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Background: The incidence of YOCRC has been rising rapidly. We recently showed that the YOCRC population has significantly different transcriptional metabolic and immune profiles than their older counterparts. In a separate study, we found that the metabolic and immune environments are affected by the sex of the patient. Based on these findings, we hypothesize that significant differences in transcriptional metabolic and immune profiles of males and females exist within the YOCRC population. The primary objective of this study was to identify those differences and compare them with the average onset colorectal cancer (AOCRC) population. Methods: Using TCGA (YOCRC N=48) and ORIEN CRC (YOCRC N=96) datasets, patients were separated into younger onset (<50) and older (>60) patient populations, comparing male and female transcriptional programs within each of the age groups. Subsequently, their transcriptional profiles were compared and assessed via differential gene expression analysis (DESeq2), gene set enrichment analysis (GSEA), immune deconvolution (TIMER2.0), and metabolic pathway analysis (MetaPhOR). These pathways were then mapped to assess transcriptional dysregulation, and patterns of predicted metabolic flux. Results: Our analysis revealed different transcriptional, metabolic, and immune signatures between males and females in differing age groups. Amongst the young patients, females were enriched for lipid metabolism (cholesterol and steroid metabolism), decreased macrophage signatures, and a proliferative phenotype. Conversely, males were enriched for glucocorticoid metabolism, urea cycle metabolites, metastasis, and CD4+ T Cell populations. Further, CTLA4 and PD-L1 response signatures were decreased in young males compared to young females, with a notable increase in inflammatory pathways. Immune deconvolution revealed no difference in the predicted infiltration of immune cells between younger males and females. In older patients (>60), females were enriched for lipid metabolism (testosterone, linoleic acid metabolism), CD8+ T cell signatures, and a proliferative phenotype. In contrast, males were enriched for lipid metabolism (cortisol), epigenetic alterations, and decreased macrophages. Like the younger population, CTLA4 and PD-L1 response signatures were decreased in older males, compared to older females, with a notable increase in inflammatory pathways. Immune deconvolution revealed decreases in CD8+ T cells and neutrophils in the predicted infiltration of older males' immune cells compared to older females. Conclusions: Our research revealed that the sex of the patient is associated with the transcriptional metabolic and immune profiles in YOCRC and AOCRC. Further translational research is needed to understand the biology better and develop effective, personalized treatment options.