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Background Conclusions Systems and Pathway Resul ts Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the US. Epidemiology studies on primary PCa cohorts in Physicians' Health Study and Health Professionals Follow-up Study (PHS and HPFS) have shown that high levels of whole-genome aneuploidy, featured by imbalanced chromosome numbers, correlate with lethal progression in PCa. However, details of the mechanisms of how aneuploidy drives PCa aggressiveness are still unclear. Here, we used the case of chromosome 8q (chr 8q, the long arm of chr 8) gain to study aneuploidy-associated prostatic malignancies. Chr 8q gains are the most frequent gain events that occur in approximately 23% of PCa cases. By using the PHS and HPFS cohorts, we modeled the increased expression of each gene located on chr 8q, for predicting the risks for lethal progression, and obtained each corresponding gene’s odds ratio (OR). By ranking the ORs, we revealed that a cholesterol biosynthesis gene, squalene monooxygenase (SQLE), is one of the top associators with lethal progression, amongst all chr 8q genes. SQLE plays a pivotal role in cholesterol synthesis. Previous lymphoma studies have shown that loss of SQLE as a cause of cholesterol auxotrophy, and when SQLE is present, squalene alters the lipid profile and protects against oxidative cell death. In our experimental study, we have used normal and cancerous TMPRSS2-ERG-driven organoid models and found that over-expression of SQLE promotes formation of invasive structures and proliferation in cancer organoids. Interestingly, overexpression of SQLE decreased the protein levels of TMPRSS2-ERG, which appeared to be independent of androgen receptor levels. We also utilized the TMPRSS2-ERG positive VCaP cell line, which harbors gains of SQLE gene copies. We found that knocking down SQLE expression significantly upregulated ERG protein levels. Our recent study has shown that ERG (or other ETS) positive prostate cancers, RITM0041128, Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the US. Epidemiology studies on primary PCa cohorts in Physicians' Health Study and Health Professionals Follow-up Study (PHS and HPFS) have shown that high levels of whole-genome aneuploidy, featured by imbalanced chromosome numbers, correlate with lethal progression in PCa. However, details of the mechanisms of how aneuploidy drives PCa aggressiveness are still unclear. Here, we used the case of chromosome 8q (chr 8q, the long arm of chr 8) gain to study aneuploidy-associated prostatic malignancies. Chr 8q gains are the most frequent gain events that occur in approximately 23% of PCa cases. By using the PHS and HPFS cohorts, we modeled the increased expression of each gene located on chr 8q, for predicting the risks for lethal progression, and obtained each corresponding gene’s odds ratio (OR). By ranking the ORs, we revealed that a cholesterol biosynthesis gene, squalene monooxygenase (SQLE), is one of the top associators with lethal progression, amongst all chr 8q genes. SQLE plays a pivotal role in cholesterol synthesis. Previous lymphoma studies have shown that loss of SQLE as a cause of cholesterol auxotrophy, and when SQLE is present, squalene alters the lipid profile and protects against oxidative cell death. In our experimental study, we have used normal and cancerous TMPRSS2-ERG-driven organoid models and found that overexpression of SQLE promotes formation of invasive structures and proliferation in cancer organoids. Interestingly, overexpression of SQLE decreased the protein levels of TMPRSS2-ERG, which appeared to be independent of androgen receptor levels. We also utilized the TMPRSS2-ERG positive VCaP cell line, which harbors gains of SQLE gene copies. We found that knocking down SQLE expression significantly upregulated ERG protein levels. Our recent study has shown that ERG (or other ETS) positive prostate cancers have a strong correlation with downregulation of fat

Increased RAD21 Promotes Prostate Cancer Development Xiaofeng A. Su1-4, *, Konrad H. Stopsack5, Daniel R. Schmidt1,6,7, Duanduan Ma8, Zhe Li7,9, Matthew G Vander Heiden1,2,10, Angelika Amon1,2,11, Lorelei A. Mucci5 1 David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 3 Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20817, USA. 4 Henry M Jackson Foundation for the Advancement of Military Medicine, Inc. Bethesda, MD 20817, USA. 5 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. 6 Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. 7 Harvard Medical School; Boston, MA 02115, USA. 8 The Barbara K. Ostrom (1978) Bioinformatics and Computing Facility in the Swanson Biotechnology Center, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. 9 Brigham and Women’s Hospital, Boston, MA 02115, USA. 10 Dana-Farber Cancer Institute, Boston, MA, 02115, USA. 11 Howard Hughes Medical Institute, Cambridge, MA 02139, USA. * Presenter; Correspondence. xsu@cpdr.org Background Summary Research Systems Results Results Prostate cancer (PCa) is one of the most common cancers among men, leading to the second cause of death for men with cancers in the US. Aneuploidy, featured by imbalanced chromosome numbers, is a hallmark of cancer. Epidemiology studies on primary PCa cohorts of Physicians' Health Study and Health Professionals Follow-up Study (PHS and HPFS) have shown that high levels of whole-genome aneuploidy correlate with lethal progression in PCa. However, the detail mechanisms of how aneuploidy drives aggressiveness of PCa are still unclear. Here, we used the case, RITM0034654, Prostate cancer (PCa) is one of the most common cancers among men, leading to the second cause of death for men with cancers in the US. Aneuploidy, featured by imbalanced chromosome numbers, is a hallmark of cancer. Epidemiology studies on primary PCa cohorts of Physicians' Health Study and Health Professionals Follow-up Study (PHS and HPFS) have shown that high levels of whole-genome aneuploidy correlate with lethal progression in PCa. However, the detail mechanisms of how aneuploidy drives aggressiveness of PCa are still unclear. Here, we used the case of chromosome 8q (chr 8q, the long arm of chr 8) gain to study aneuploidyassociated prostatic malignancies. Chr 8q gains are the most frequently gain events that occur in around 23% of PCa cases. By using the PHS and HPFS cohorts, we modeled the increased expression of each gene located on chr 8q, for predicting the risks for lethal progression, and obtained the odds ratio (OR) for each. Then, we ranked the ORs for lethal progression and identified several important genes highly associated with lethality when overexpressed. Among them, the cohesin subunit gene, RAD21, is one of the top associators. Increased RAD21 mRNA level, per se, is highly correlated with lethality in all PCa cases, and the lethality is synergistically aggravated in the cases with both increased RAD21 expression and chr 8q gains. indicating that RAD21 cooperates with other chr 8q genes to drive cancer progression and chr 8q gains. To determine how RAD21 overexpression promotes PCa, we studied the effect of overexpression of RAD21 in early prostatic oncogenic events. We utilized the isogenic mouse prostate organoid models carrying an inducible the fusion-oncogene, TMPRSS2-ERG (T-ERG), which 50% of PCa cases harbor. We found that induction of T-ERG leads to a strong oncogenic replication stress at an early stage. Such stress results in an increase in apoptosis and growth impairment in these primary organoids. Overexpression of RAD21, mimicking the