Proteogenomic and observational evidence implicate ANGPTL4 as a potential therapeutic target for colorectal cancer prevention

Background: Preclinical, observational, and genetic epidemiological evidence implicate circulating lipids in cancer development. The role of approved and emerging lipid-perturbing medications in cancer risk is unclear. Patients and methods: We employed cis-Mendelian randomization (MR) and colocalisation to evaluate the role of 5 lipid-perturbing drug targets (ANGPTL3, ANGPTL4, APOC3, CETP, PCSK9) in risk of 5 cancers (breast, colorectal, head and neck, ovarian, prostate) in up to 319,661 cases and 348,078 controls. We further triangulated findings using direct measures of pre-diagnostic protein targets in case-cohort analyses in the European Prospective Investigation into cancer and Nutrition (EPIC). To gain mechanistic insight into the role of ANGPTL4 in carcinogenesis, we examined the impact of the ANGPTL4 p.E40K loss-of-function variant on differential gene expression in normal colon tissue in the BarcUVa-Seq project. Finally, we evaluated the association of ANGPTL4 gene expression in colon tumour tissue with all-cause mortality in The Cancer Genome Atlas (TCGA). Results: In analysis of 78,473 cases and 107,143 controls, genetically-proxied circulating ANGPTL4 inhibition was associated with a reduced risk of colorectal cancer (OR per SD decrease: 0.76, 95% CI 0.66-0.89, P = 5.52 x 10-4, colocalisation posterior probability = 0.83). This association was replicated in the EPIC cohort using pre-diagnostic circulating ANGPTL4 concentrations in 977 incident colorectal cancer cases and 4,080 sub-cohort members (HR per log10 decrease: 0.92, 95% CI 0.85-0.99, P = 0.02). In gene set enrichment analysis of differential gene expression in 445 normal colon tissue samples, ANGPTL4 loss-of-function was associated with down-regulation of several biological pathways implicated in cancer (FDR P < 0.05), including those involved in cellular proliferation, epithelial-to-mesenchymal transition, and bile acid metabolism. In analysis of 465 colon cancer patients, lower ANGPTL4 expression in tumour tissue was associated with reduced risk of all-cause mortality (HR per log2 decrease: 0.85, 95% CI 0.73-0.99; P = 0.04). There was little evidence of association of genetically-proxied inhibition of ANGPTL4 or other lipid targets with the other cancer outcomes evaluated. Conclusion: Our integrative proteogenomic and observational analyses suggest a protective role of lower circulating ANGPTL4 concentrations in colorectal cancer risk. These findings support further evaluation of ANGPTL4, an emerging drug target for hypertriglyceridemia, as a potential therapeutic target for colorectal cancer prevention.