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.
Proceedings of the National Academy of Sciences of the United States of America. 2024 Aug 27 [Epub]
Xiaofeng A Su, Konrad H Stopsack, Daniel R Schmidt, Duanduan Ma, Zhe Li, Paul A Scheet, Kathryn L Penney, Tamara L Lotan, Wassim Abida, Elise G DeArment, Kate Lu, Thomas Janas, Sofia Hu, Matthew G Vander Heiden, Massimo Loda, Monica Boselli, Angelika Amon, Lorelei A Mucci
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139., Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115., Division of Genetics, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115., Department of Epidemiology, The University of Texas MD Anderson Cancer Center, TX 77030., Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21218., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20817., Weil Cornell Medicine, New York Presbyterian-Weill Cornell Campus, New York, NY 10065.