Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response
Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response
Abstract Insights into oncogenesis derived from cancer susceptibility loci could facilitate better cancer management and treatment through precision oncology. However, therapeutic applications have thus far been limited by our current lack of understanding regarding both their interactions with somatic cancer driver mutations and their influence on tumorigenesis. Here, by integrating germline datasets relating to cancer susceptibility with tumour data capturing somatically-acquired genetic variation, we provide evidence that single nucleotide polymorphism (SNPs) and somatic mutations in the p53 tumor suppressor pathway can interact to influence cancer development, progression and treatment response. We go on to provide human genetic evidence of a tumor-promoting role for the pro-survival activities of p53, which supports the development of more effective therapy combinations through their inhibition in cancers retaining wild-type p53. SignificanceWe describe significant interactions between heritable and somatic genetic variants in the p53 pathway that affect cancer susceptibility, progression and treatment response. Our results offer evidence of how cancer susceptibility SNPs can interact with cancer driver genes to affect cancer progression and identify novel therapeutic targets.
Grochola Lukasz F.、Turnbull Clare、Domingo Enric、Selfe Joanna、Wang Xuting、Palles Claire、Protheroe Andrew、Pagadala Meghana、Tomlinson Ian、Zhang Ping、Stracquadanio Giovanni、Brown Katherine、Richter Philipp、Bond Elisabeth、Sahgal Natasha、Nornes Svanhild、Bell Douglas A.、Zeron-Medina Jorge、Kar Siddhartha、Pharoah Paul、Sims David、Maughan Tim、Millar Val、Ryan Anderson、Loveday Chey、Kitchen-Smith Isaac、Jansen Rick、Wallace Marsha、Ebner Daniel、Moore Samantha、Bond Gareth、Jiang Yanyan、Xiong Lingyun、Shipley Janet、De Val Sarah、Surakhy Mirvat、Blagden Sarah P.、Carter Hannah
Institute for Surgical Pathology, University Hospital of ZurichDivision of Genetics and Epidemiology, The Institute of Cancer ResearchDepartment of Oncology, University of OxfordSarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer ResearchEnvironmental Epigenomics and Disease Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences-National Institutes of HealthInstitute of Cancer and Genomic Sciences, University of BirminghamOxford Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation TrustDepartment of Medicine, University of CaliforniaInstitute of Cancer and Genomic Sciences, University of BirminghamLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical Medicine||Institute of Quantitative Biology, Biochemistry, and Biotechnology, SynthSys, School of Biological Sciences, University of EdinburghWeatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital||Division of Virology, Department of Pathology, University of CambridgeLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineEnvironmental Epigenomics and Disease Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences-National Institutes of HealthVall d?ˉHebron University Hospital, Oncology DepartmentDepartment of Public Health and Primary Care, University of CambridgeDepartment of Public Health and Primary Care, University of CambridgeWeatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe HospitalDepartment of Oncology, University of OxfordTarget Discovery Institute, University of Oxford, Nuffield Department of MedicineCRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of OncologyDivision of Genetics and Epidemiology, The Institute of Cancer ResearchLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Psychiatry, Amsterdam NeuroscienceLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineTarget Discovery Institute, University of Oxford, Nuffield Department of MedicineLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineCRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of OncologyLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineSarcoma Molecular Pathology Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer ResearchLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineLudwig Institute for Cancer Research, University of Oxford, Nuffield Department of Clinical MedicineDepartment of Oncology, University of OxfordDepartment of Medicine, University of California
肿瘤学遗传学基础医学
Grochola Lukasz F.,Turnbull Clare,Domingo Enric,Selfe Joanna,Wang Xuting,Palles Claire,Protheroe Andrew,Pagadala Meghana,Tomlinson Ian,Zhang Ping,Stracquadanio Giovanni,Brown Katherine,Richter Philipp,Bond Elisabeth,Sahgal Natasha,Nornes Svanhild,Bell Douglas A.,Zeron-Medina Jorge,Kar Siddhartha,Pharoah Paul,Sims David,Maughan Tim,Millar Val,Ryan Anderson,Loveday Chey,Kitchen-Smith Isaac,Jansen Rick,Wallace Marsha,Ebner Daniel,Moore Samantha,Bond Gareth,Jiang Yanyan,Xiong Lingyun,Shipley Janet,De Val Sarah,Surakhy Mirvat,Blagden Sarah P.,Carter Hannah.Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response[EB/OL].(2025-03-28)[2025-05-12].https://www.biorxiv.org/content/10.1101/835918.点此复制
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