Trans-ancestry analysis in over 799,000 individuals yields new insights into the genetic etiology of colorectal cancer.

BACKGROUND: Recent studies have demonstrated the relevance of circulating factors in the occurrence and development of colorectal cancer (CRC); however, the causal relationship remains unclear. METHODS: Summary-level data for CRC were obtained from the UK Biobank (5,657 cases and 372,016 controls), FinnGen cohort (3,022 cases and 215,770 controls), and BioBank Japan Project (BBJ, 7,062 cases and 195,745 controls). Thirty-two peripheral markers with consistent definitions were collected from the three biobanks. Mendelian randomization (MR) was used to evaluate the causal effect of circulating factors on CRC. The effects from the three consortiums were combined using trans-ancestry meta-analysis methods. RESULTS: Our analysis provided compelling evidence for the causal association of higher genetically predicted eosinophil cell count (EOS, odds ratio [OR], 0.8639; 95% confidence interval [CI] 0.7922-0.9421) and red cell distribution width (RDW, OR, 0.9981; 95% CI, 0.9972-0.9989) levels with a decreased risk of CRC. Additionally, we found suggestive evidence indicating that higher levels of total cholesterol (TC, OR, 1.0022; 95% CI, 1.0002-1.0042) may increase the risk of CRC. Conversely, higher levels of platelet count (PLT, OR, 0.9984; 95% CI, 0.9972-0.9996), total protein (TP, OR, 0.9445; 95% CI, 0.9037-0.9872), and C-reactive protein (CRP, OR, 0.9991; 95% CI, 0.9983-0.9999) may confer a protective effect against CRC. Moreover, we identified six ancestry-specific causal factors, indicating the necessity of considering patients' ancestry backgrounds before formulating prevention strategies. CONCLUSIONS: MR findings support the independent causal roles of circulating factors in CRC, which might provide a deeper insight into early detection of CRC and supply potential preventative strategies.

Development of a novel hypoxia-immune-related LncRNA risk signature for predicting the prognosis and immunotherapy response of colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most common digestive system tumors worldwide. Hypoxia and immunity are closely related in CRC; however, the role of hypoxia-immune-related lncRNAs in CRC prognosis is unknown. Methods: Data used in the current study were sourced from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) databases. CRC patients were divided into low- and high-hypoxia groups using the single-sample gene set enrichment analysis (ssGSEA) algorithm and into low- and high-immune groups using the Estimation of STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm. Differentially expressed lncRNAs (DElncRNAs) between low- and high-hypoxia groups, low- and high-immune groups, and tumor and control samples were identified using the limma package. Hypoxia-immune-related lncRNAs were obtained by intersecting these DElncRNAs. A hypoxia-immune-related lncRNA risk signature was developed using univariate Cox regression and least absolute shrinkage and selection operator (LASSO) analyses. The tumor microenvironments in the low- and high-risk groups were evaluated using ssGSEA, ESTIMATE, and the expression of immune checkpoints. The therapeutic response in the two groups was assessed using TIDE, IPS, and IC50. A ceRNA network based on signature lncRNAs was constructed. Finally, we used RT-qPCR to verify the expression of hypoxia-immune-related lncRNA signatures in normal and cancer tissues. Results: Using differential expression analysis, and univariate Cox and LASSO regression analyses, ZNF667-AS1, LINC01354, LINC00996, DANCR, CECR7, and LINC01116 were selected to construct a hypoxia-immune-related lncRNA signature. The performance of the risk signature in predicting CRC prognosis was validated in internal and external datasets, as evidenced by receiver operating characteristic curves. In addition, we observed significant differences in the tumor microenvironment and immunotherapy response between low- and high-risk groups and constructed a CECR7-miRNA-mRNA regulatory network in CRC. Furthermore, RT-qPCR results confirmed that the expression patterns of the six lncRNA signatures were consistent with those in TCGA-CRC cohort. Conclusion: Our study identified six hypoxia-immune-related lncRNAs for predicting CRC survival and sensitivity to immunotherapy. These findings may enrich our understanding of CRC and help improve CRC treatment. However, large-scale long-term follow-up studies are required for verification.