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Published on: September 30, 2016
Proteogenomic and observational evidence implicate ANGPTL4 as a potential therapeutic target for colorectal cancer
James Yarmolinsky1, Matthew A Lee2, Evelyn Lau3
1Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
Background:
The role of lipid-perturbing medications in cancer risk is unclear.
Methods:
We employed cis-Mendelian randomization and colocalization to evaluate the role of 5 lipid-perturbing drug targets (ANGPTL3, ANGPTL4, APOC3, CETP, and PCSK9) in risk of 5 cancers (breast, colorectal, head and neck, ovarian, and prostate). We triangulated findings using pre-diagnostic protein measures in prospective analyses in EPIC (977 colorectal cancer cases, 4080 sub-cohort members) and the UK Biobank (860 colorectal cancer cases, 50 177 controls). 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 BarcUVa-Seq. Finally, we evaluated the association of colon tumor ANGPTL4 expression with cancer-specific mortality in TCGA.
Results:
In analysis of 78 473 cases and 107 143 controls, genetically proxied circulating ANGPTL4 inhibition was associated with reduced colorectal cancer risk (ORSD decrease = 0.76, 95% confidence interval [CI] = 0.66 to 0.89, P = 5.52 × 10-4, PPcolocalization = 0.83). This association was replicated using pre-diagnostic circulating ANGPTL4 concentrations in EPIC (hazard ratio [HR]log10 decrease = 0.91, 95% CI = 0.84 to 0.98, P = .01) and the UK Biobank (HRSD decrease = 0.93, 95% CI = 0.86 to 0.99, P = .03). In gene-set enrichment analysis of differential gene expression in 445 colon tissue samples, ANGPTL4 loss-of-function down-regulated several cancer-related biological pathways (PFDR < .05), including those involved in cellular proliferation, epithelial-to-mesenchymal transition, and bile acid metabolism. In analysis of 465 colon cancer patients, lower ANGPTL4 tumor expression was associated with reduced colorectal cancer-specific mortality risk (HRlog2 decrease = 0.66, 95% CI = 0.50 to 0.87, P = 2.92 × 10-3).
Conclusions:
Our integrative proteogenomic and observational analyses suggest a potential protective role of lower circulating ANGPTL4 concentrations in colorectal cancer risk. These findings support further evaluation of ANGPTL4 as a therapeutic target for colorectal cancer prevention.
Insights
Lowering circulating ANGPTL4 may reduce colorectal cancer risk. This study suggests ANGPTL4 as a potential therapeutic target for colorectal cancer prevention, supported by genetic and observational data.
Area of Science:
- Genetics and Genomics
- Cancer Biology
- Pharmacology
Background:
- The relationship between lipid-modulating medications and cancer risk remains unclear.
- Investigating specific drug targets involved in lipid metabolism is crucial for understanding cancer risk.
- ANGPTL4 is a key target in lipid metabolism with an unknown role in cancer.
Purpose of the Study:
- To investigate the role of five lipid-perturbing drug targets (ANGPTL3, ANGPTL4, APOC3, CETP, PCSK9) in the risk of five major cancers.
- To explore the mechanistic link between ANGPTL4 and colorectal cancer development and progression.
- To evaluate ANGPTL4 as a potential therapeutic target for colorectal cancer prevention.
Main Methods:
- Utilized cis-Mendelian randomization and colocalization to assess the association between lipid drug targets and cancer risk.
- Employed prospective analyses with pre-diagnostic protein measures in EPIC and UK Biobank cohorts for validation.
- Conducted gene-set enrichment analysis and evaluated tumor ANGPTL4 expression in TCGA for mechanistic and prognostic insights.
Main Results:
- Genetically predicted lower ANGPTL4 levels were associated with reduced colorectal cancer risk (ORSD 0.76).
- This association was confirmed by prospective analyses in EPIC and UK Biobank cohorts.
- ANGPTL4 loss-of-function downregulated cancer-related pathways, and lower tumor ANGPTL4 expression correlated with reduced colorectal cancer mortality.
Conclusions:
- Integrative proteogenomic and observational data suggest lower circulating ANGPTL4 concentrations may protect against colorectal cancer.
- Findings support the potential of ANGPTL4 as a therapeutic target for colorectal cancer prevention.
- Further research into ANGPTL4's role in carcinogenesis is warranted.
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