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

By integrating findings from large-scale omics analyses with experimental tests, this study aims to decipher susceptibility genes and the underlying biological mechanisms involved in the development of colorectal cancer (CRC). We first conducted a trans-ancestry transcriptome-wide association study (TWAS) among 57,402 CRC cases and 119,110 controls, aiming to examine how altered gene expression influences CRC risk in European and Asian populations. Then, functional experiments in (i) CRC cell lines and (ii) tumor xenografts were conducted to examine potential underlying mechanisms involved in colorectal carcinogenesis. Further, a drug sensitivity test was employed to explore possible clinical implications for CRC treatment. The TWAS identified 67 genes highly associated with CRC risk, 23 of which were novel findings. Functional annotation of variants within TWAS-identified loci revealed that the majority (93.6%) showed evidence of transcriptional regulatory mechanisms via proximal promoter or distal enhancer-promoter interactions. Among the identified susceptibility genes, splicing factor 3a subunit 3 (SF3A3) may act as an oncogene on the basis that overexpression of this gene was significantly associated with increased risk of CRC (P = 5.75 × 10^-11). Further cell and animal experiments confirmed that SF3A3 plays an oncogenic role in CRC development, and the underlying biological mechanism is likely to be related to its anti-apoptosis effect. The drug sensitivity test suggested that phenethyl isothiocyanate (PEITC) targeting SF3A3 can inhibit CRC progression. This study identified novel CRC susceptibility genes and potential biological mechanisms of SF3A3 involved in CRC development, providing important insight into the etiology and potential leads to the treatment of CRC.