Genetically Proxied Inhibition of Cholesterol-Lowering Drug Targets and Survival in HPV-Positive and Non-HPV-Driven Head and Neck Cancer: A Multicentre MR Study
Related Experiment Video
Updated: Jul 3, 2026
Chromogenic In Situ Hybridization as a Tool for HPV-Related Head and Neck Cancer Diagnosis
Published on: June 14, 2019
Danni Cheng1,2, Katrina Hueniken2, Tianzhichao Hou2,3
1Department of Otolaryngology-Head and Neck Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
Background:
Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major low-density lipoprotein cholesterol (LDL-C)-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV-driven HNSCCs.
Methods:
We proxied lifelong LDL-C lowering using 55 cis-acting single-nucleotide polymorphisms in HMGCR, NPC1L1, PCSK9, and LDL-receptor (LDLR) from the updated 2021 Global Lipids Genetics Consortium and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multicentre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV-driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumor stage and treatment, assessed collider bias using an external HNSCC incidence genome-wide association study, and examined between-center heterogeneity and colocalization.
Results:
Using the updated Global Lipids Genetic Consortium 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but nonsignificant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis [inverse variance weighted (IVW) HR = 0.19; 95% confidence interval (CI), 0.03-1.18; P = 0.08], with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR = 1.68; 95% CI, 0.78-3.63; P = 0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant.
Conclusions:
These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC.
Impact:
HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.
Insights
Genetically inhibiting HMGCR may improve survival in HPV-positive head and neck cancers. Other cholesterol drug targets did not show a clear survival benefit in this study.
Area of Science:
- Genetics
- Oncology
- Metabolic Pathways
Background:
- Cholesterol pathways are implicated in head and neck squamous cell carcinoma (HNSCC) progression.
- Existing evidence on the prognostic impact of cholesterol pathways in HNSCC is inconsistent.
- This study investigates the role of cholesterol metabolism in HNSCC survival.
Purpose of the Study:
- To determine if genetically proxied inhibition of major LDL-C-lowering drug targets influences overall survival (OS) in HPV-positive and non-HPV driven HNSCC.
- To assess the association between circulating lipid traits and HNSCC prognosis.
- To explore the causal relationship between cholesterol pathways and HNSCC outcomes using Mendelian randomization.
Main Methods:
- Utilized Mendelian randomization (MR) with 55 cis-acting SNPs from the Global Lipids Genetics Consortium (GLGC) 2021.
- Proxied lifelong low-density lipoprotein cholesterol (LDL-C) lowering via HMGCR, NPC1L1, PCSK9, and LDLR.
- Estimated effects on OS in 4,869 HNSCC cases (1,291 HPV-positive; 3,578 non-HPV driven) using two-sample MR and Cox models.
- Conducted sensitivity analyses for tumor stage, treatment, collider bias, and heterogeneity.
Main Results:
- Genetically proxied HMGCR inhibition showed a trend towards improved OS in HPV-positive oropharyngeal HNSCC (IVW HR=0.19, P=0.08).
- No significant association was found for HMGCR inhibition in non-HPV-driven HNSCC (IVW HR=1.68, P=0.19).
- No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum.
Conclusions:
- Suggestive evidence indicates that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC.
- HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC.
- Clear survival effects of other cholesterol-lowering targets were not supported by this study.
