O43 Trans-ancestry transcriptome-wide association study to uncover novel susceptibility genes and therapeutic targets for colorectal cancer

Introduction

Genome-wide association studies (GWASs) have revealed hundreds of common single nucleotide polymorphisms (SNPs) and susceptibility genes for colorectal cancer (CRC). For most susceptibility locus, the underlying biological mechanisms involved in colorectal carcinogenesis remain unclear. We conducted a trans-ancestry transcriptome-wide association study (TWAS), aiming to illustrate how altered gene expression influences CRC risk.

Methods

We first carried out a trans-ancestry meta-analysis through combining summary statistics from large-scale CRC GWASs conducted in European (20,049 cases and 22,661 controls) and Asian (19,597 cases and 51,398 controls) populations. TWAS analysis was then performed by integrating gene-expression prediction models generated from colon tissues and blood samples with GWAS summary data to evaluate associations between genetically predicted gene expression and CRC risk. Functional experiments both in CRC cells and tumor xenografts were conducted to examine the underlying mechanisms involved in colorectal carcinogenesis. Further, a drug sensitivity test was employed to explore potential clinical implications for CRC treatment.

Results

The TWAS identified a total of 50 differentially expressed genes highly associated with CRC risk, and eleven of them (ASPDH, AXIN1, CCDC28A, CNPY4, CRTC3, CYB5D1, DENND4C, FAM89B, FNIP2, RUFY2, SOX4) were novel findings. Annotation of putative functional variants within TWAS-identified locus revealed that over half (63.8%) showed evidence of transcriptional regulatory mechanisms via proximal promoter or distal enhancer-promoter interactions. Over-expression of gene-splicing factor 3a subunit 3 (SF3A3) was significantly associated with increased risk of CRC (P = 1.35×10^-8). Further cell and animal experiments confirmed that SF3A3 plays an oncogenic role in CRC development, and the underlying biological mechanism is related to its anti-apoptosis effect. The drug sensitivity test revealed that phenethyl isothiocyanate (PEITC) targeting SF3A3 could inhibit CRC progression.

Conclusions

This study identified novel CRC susceptibility genes and explored potential biological mechanisms involved in CRC development, providing important insight into the etiology and treatment of CRC.