RAD21 promotes oncogenesis and lethal progression of prostate cancer

Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q...

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Veröffentlicht in:Proceedings of the National Academy of Sciences - PNAS Jg. 121; H. 36; S. e2405543121
Hauptverfasser: Su, Xiaofeng A, Stopsack, Konrad H, Schmidt, Daniel R, Ma, Duanduan, Li, Zhe, Scheet, Paul A, Penney, Kathryn L, Lotan, Tamara L, Abida, Wassim, DeArment, Elise G, Lu, Kate, Janas, Thomas, Hu, Sofia, Vander Heiden, Matthew G, Loda, Massimo, Boselli, Monica, Amon, Angelika, Mucci, Lorelei A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 03.09.2024
Schlagworte:
Aneuploidy
Carcinogenesis - genetics
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Chromosomes, Human, Pair 8 - genetics
Disease Progression
DNA Damage
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Gene Expression Regulation, Neoplastic
Humans
Male
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - metabolism
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
clinical outcomes
prostate cancer
DNA damage
RAD21
organoid
ISSN:1091-6490, 1091-6490
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Zusammenfassung:Higher levels of aneuploidy, characterized by imbalanced chromosome numbers, are associated with lethal progression in prostate cancer. However, how aneuploidy contributes to prostate cancer aggressiveness remains poorly understood. In this study, we assessed in patients which genes on chromosome 8q, one of the most frequently gained chromosome arms in prostate tumors, were most strongly associated with long-term risk of cancer progression to metastases and death from prostate cancer (lethal disease) in 403 patients and found the strongest candidate was cohesin subunit gene, , with an odds ratio of 3.7 (95% CI 1.8, 7.6) comparing the highest vs. lowest tertiles of mRNA expression and adjusting for overall aneuploidy burden and Gleason score, both strong prognostic factors in primary prostate cancer. Studying prostate cancer driven by the oncogenic fusion, found in about half of all prostate tumors, we found that increased alleviated toxic oncogenic stress and DNA damage caused by oncogene expression. Data from both organoids and patients indicate that increased RAD21 thereby enables aggressive tumors to sustain tumor proliferation, and more broadly suggests one path through which tumors benefit from aneuploidy.
Bibliographie:ObjectType-Article-1
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.2405543121