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
Year: 2026
Type: article
Study design: Observational Study
Abstract: 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.
Authors: Danni Cheng, Katrina Hueniken, Tianzhichao Hou, Tao Shu, Osvaldo Espin-Garcia, Tom Dudding, Mark Gormley, James D. McKay, John R. de Almeida, Andrew J. Hope, Anna Spreafico, Shao Hui Huang, Lea Schroeder, Tim Waterboer, D. Neil Hayes, Shama Virani, Paul Brennan, Miranda Pring, Andrew F. Olshan, Brenda Diergaarde, Gary J. Macfarlane, Pagona Lagiou, Areti Lagiou, Jerry Polesel, Antonio Agudo, Laia Alemany, Wolfgang Ahrens, Claire M. Healy, David I. Conway, Cristina Canova, Ivana Holcatova, Jianjun Ren, Yu Zhao, Rayjean J. Hung, Alison M. Mondul, Wei Xu, Geoffrey Liu
Institutions: University Health Network, Sichuan University, West China Medical Center of Sichuan University, Princess Margaret Cancer Centre, West China Hospital of Sichuan University, Boston Children's Hospital, Harvard University, Western University, University Of Bristol Dental Hospital, University of Bristol, World Health Organization, Centre international de recherche sur le cancer, University of Toronto, German Cancer Research Center, University of Tennessee Health Science Center, University of North Carolina at Chapel Hill, University of Pittsburgh, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, University of Aberdeen, National and Kapodistrian University of Athens, University of West Attica, Centro di Riferimento Oncologico, Institut Català d'Oncologia, Institut d'Investigació Biomédica de Bellvitge, University of Bremen, Trinity College Dublin, University of Glasgow, University of Padua, Charles University, University Hospital in Motol, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Michigan
Language: English
Topic: Head and Neck Cancer Studies
Subfield: Otorhinolaryngology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Compagnia di San Paolo, University of Pittsburgh, Princess Margaret Hospital Foundation, Cancer Research UK, National Institute for Health and Care Research, European Commission, Canada Research Chairs, National Natural Science Foundation of China, Department of Science and Technology of Sichuan Province, Sichuan University, National Institutes of Health, NIHR BioResource, Canadian Cancer Society Research Institute, West China Hospital, Sichuan University, National Cancer Institute, National Institute of Dental and Craniofacial Research
Awards: G1411592995, G2308828585, G2675649516, G3344456887, G34221693, G3693885668, G4444790347, G479108254, G5324144389, The role of germline and somatic DNA mutations in oral and oropharyngeal cancers, Evidence based health care for major congenital and acquired problems of the head and neck, G633032242, G6966134840, G741073515, G7831930824, G8078330568, G9000010196, G9000080943
OpenAlex ID: W7167022007
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