220P - The role of fucosyltransferase 1 (FUT1) in CRC as a putative prognostic and predictive biomarker

Background

Likenesses between fetal and cancerous tissues have been proposed with some of these similarities being conferred by the means of glycosylation. Analysis of genes involved in this process might be helpful to find potential novel targets in colorectal cancer (CRC).

Methods

Publicly available data of CRC patients from TCGA (n=455) were screened for survival differences according to mRNA levels of glycosylation-associated genes, stratifying them into low and high groups for differential gene expression analysis. Cell estimates were analyzed using single-cell RNAseq in publicly available data sets. Using data from the Genomics of Drug Sensitivity in Cancer (GDSC), compounds were screened for differences in treatment response between groups. Data from the CTPAC and COAD SILU study were used to confirm results.

Results

One candidate gene - Fucosyltransferase 1 (FUT1) - was identified that yielded a difference in median overall survival (high: 99.9 mo vs. low: 49.4 mo, p=0.0095). Baseline characteristics between groups showed no significant differences for age, sex, MSI status or TMB. Gene set enrichment analysis revealed upregulation of genes involved in DNA repair systems and downregulation of genes related to immune function (e.g. leukocyte proliferation, leukocyte cell-cell adhesion). Immune cell deconvolution showed negative association between FUT1 levels, B cells and macrophages – conversely, FUT1 levels correlated positively with naïve CD8⁺ T cells. ScRNAseq revealed high FUT1 mRNA levels in cancer and endothelial cells. FUT1 high tumors were characterized by an activation of MAP kinase, VEGF, TGF-beta, estrogen and PI3K/mTOR signaling, whereas p53, Trail, hypoxia, androgen and NFkB signaling were decreased. Differences in predicted IC50 levels were found for inhibitors of PI3K/mTOR and MAP kinase.

Conclusions

We identified high FUT1 expression as a novel, independent poor prognosticator in CRC. Impaired prognosis might be attributable to changes in DNA repair mechanisms and cell cycle as well as immunogenicity. In silico analysis revealed therapeutic vulnerability towards PI3K/mTOR and MAP kinase inhibition. Validation studies using in vitro methods and an independent clinical trial dataset are currently ongoing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.