O43 Trans-ancestry transcriptome-wide association study to uncover novel susceptibility genes and therapeutic targets for colorectal cancer
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".