| Abstract: |
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, RAD21, 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 TMPRSS2-ERG oncogenic fusion, found in about half of all prostate tumors, we found that increased RAD21 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. © 2024 the Author(s). |
| Keywords: |
immunohistochemistry; controlled study; protein expression; aged; dna binding protein; gene mutation; human cell; major clinical study; overall survival; genetics; dna-binding proteins; cancer growth; cancer risk; follow up; cancer grading; dna replication; cell proliferation; cell cycle protein; metabolism; cell cycle proteins; dna damage; cell cycle progression; dna repair; gene overexpression; apoptosis; gene expression; confocal microscopy; nuclear protein; genotype; antineoplastic activity; immunofluorescence; pathology; chromosomes, human, pair 8; histology; cancer mortality; carcinogenesis; nuclear proteins; prostate cancer; gleason score; prostatic neoplasms; questionnaire; gene expression regulation; tumor suppressor gene; gene expression regulation, neoplastic; genetic transfection; prostatectomy; disease progression; prostate tumor; oncogene proteins, fusion; upregulation; tissue microarray; tumor growth; genetic risk; transurethral resection; chromosome 8; karyotype; aneuploidy; disease exacerbation; health care access; lethality; rna extraction; chromosome 8q; schizosaccharomyces pombe; chromosome arm; clinical outcome; aggressiveness; comet assay; chromosome number; cancer prognosis; clinical outcomes; physiological stress; humans; human; male; article; immunofluorescence assay; organoid; prostate ventral lobe; tmprss2-erg fusion protein, human; neoplastic cell transformation; oncogene fusion protein; rad21; rad21 protein, human
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