The Genomic Landscape of Prostate Cancer Brain Metastases
The Genomic Landscape of Prostate Cancer Brain Metastases
Abstract Lethal prostate cancer commonly metastasizes to bone, lymph nodes, and visceral organs but with more effective therapies, there is an increased frequency of metastases to the brain. Little is known about the genomic drivers of prostate cancer brain metastases (PCBM). To address this, we conducted a comprehensive multi-regional, genomic, and targeted transcriptomic analysis of PCBM from 28 patients. We compared whole-exome and targeted RNA sequencing with matched primary tumors when available (n = 10) and with publicly available genomic data from non-brain prostate cancer metastases (n = 416). In addition to common alterations in TP53, AR, RB1, and PTEN, we identified highly significant enrichment of mutations in NF1 (25% cases (6/28), q = 0.049, 95% CI = 2.38 – 26.52, OR = 8.37) and RICTOR (17.9% cases (5/28), q = 0.01, 95% CI = 6.74 – 480.15, OR = 43.7) in PCBM compared to non-brain prostate cancer metastases, suggesting possible activation of the druggable pathways RAS/RAF/MEK/ERK and PI3K/AKT/mTOR, respectively. Compared to non-brain prostate cancer metastases, PCBM were almost three times as likely to harbor DNA homologous repair (HR) alterations (42.9% cases (12/28), p =0.016, 95% CI = 1.17 – 6.64, OR = 2.8). When considering the combination of somatic mutations, copy number alteration, and Large-scale State Transitions, 64.3% of patients (18/28) were affected. HR alterations may be critical drivers of brain metastasis that potentially provide cancer cells a survival advantage during re-establishment in a special microenvironment. We demonstrate that PCBM have genomic dependencies that may be exploitable through clinical interventions including PARP inhibition.
Rushing Elisabeth J.、Rodriguez Antonio、Akhoundova Dilara、Maletti Sina、Cyrta Joanna、Hewer Ekkehard、Amstutz Ursula、Garofoli Andrea、Tomlins Scott A.、Genitsch Vera、Grobholz Rainer、Fischer Ingeborg、Jochum Wolfram、Sommer Silke Gillessen、Rubin Mark A.、Paradiso Viola、Fleischmann Achim、Ferguson Alison、Cathomas Gieri、Bubendorf Lukas、Gallon John、Moch Holger、Ng Charlotte K.Y.、Piscuoglio Salvatore
Institute of Neuropathology, University Hospital ZurichDepartment for BioMedical Research, University of Bern||Institute of Pathology, University of BernDepartment of Medical Oncology and Hematology, University Hospital ZurichDepartment for BioMedical Research, University of BernInstitut Curie, University Paris Sciences et Lettres, Department of PathologyInstitute of Pathology, University of BernDepartment of Clinical Chemistry, Inselspital, Bern University Hospital, University of BernInstitute of Medical Genetics and Pathology, University Hospital Basel, University of BaselUniversity of MichiganInstitute of Pathology, University of BernInstitute of Pathology, Cantonal Hospital AarauInstitute of Pathology, Cantonal Hospital AarauInstitute of Pathology, Cantonal Hospital St. GallenOncology Institute of Southern Switzerland, Hospital San Giovanni||Department of Oncology, Cantonal Hospital St. Gallen||Division of Cancer Sciences, University of ManchesterDepartment for BioMedical Research, University of Bern||Bern Center for Precision Medicine, Inselspital, Bern University Hospital, University of BernInstitute of Medical Genetics and Pathology, University Hospital Basel, University of BaselInstitute of Pathology, Cantonal Hospital ThurgauDepartment for BioMedical Research, University of Bern||Department of Oncology, Ludwig Cancer Centre, University of LausanneInstitute of Pathology, Cantonal Hospital BasellandDepartment of Medical Oncology and Hematology, University Hospital ZurichVisceral Surgery Research Laboratory, Department of Biomedicine, University of BaselDepartment of Pathology and Molecular Pathology, University Hospital ZurichDepartment for BioMedical Research, University of BernVisceral Surgery Research Laboratory, Department of Biomedicine, University of Basel||Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel
肿瘤学基础医学分子生物学
prostate cancerbrain metastasesNF1RICTORhomologous repairgenomicsPARPBRCA2BRCA1ATM
Rushing Elisabeth J.,Rodriguez Antonio,Akhoundova Dilara,Maletti Sina,Cyrta Joanna,Hewer Ekkehard,Amstutz Ursula,Garofoli Andrea,Tomlins Scott A.,Genitsch Vera,Grobholz Rainer,Fischer Ingeborg,Jochum Wolfram,Sommer Silke Gillessen,Rubin Mark A.,Paradiso Viola,Fleischmann Achim,Ferguson Alison,Cathomas Gieri,Bubendorf Lukas,Gallon John,Moch Holger,Ng Charlotte K.Y.,Piscuoglio Salvatore.The Genomic Landscape of Prostate Cancer Brain Metastases[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/2020.05.12.092296.点此复制
评论