Joseph Choi
Pronouns: He/Him
Research Mentor(s): Jean Tien
Co-Presenter:
Research Mentor School/College/Department: Pathology – MCTP / Medicine
Presentation Date: April 20
Presentation Type: Poster
Session: Session 5 – 3:40pm – 4:30 pm
Room: League Ballroom
Authors: Joseph Choi, Palak Shah, Yunhui Cheng, Abhijit Parolia, Sanjana Eyunni, Rahul Mannan, Andrew Goodrum, Shuqin Li, Jean Tien, Arul Chinnaiyan
Presenter: 42
Abstract
Background: In the U.S., prostate cancer accounts for the second most cancer-related deaths in men. Although metastatic castration-resistant prostate cancer (mCRPC) occurs in 1.6-2.1 per 100 PCa cases, mCRPC accounts for 20% of all-cause mortality in prostate cancer. Using high-throughput sequencing of 360 mCRPC tumors, we identified a novel subtype of prostate cancer, which is characterized by biallelic inactivating mutations in CDK12. CDK12 loss was associated with a genomic instability pattern characterized by focal tandem duplications, gene fusions and neoantigen generation. In the dataset, CDK12 inactivation was mutually exclusive with several known PCa drivers (eg ETS fusions; MMRD and SPOP mutations); however coexisted with other mutations including inactivation of TP53. While this clinical data suggested CDK12 could act as a tumor suppressor gene, whether CDK12 loss actually caused cancer—alone or in the context of other cancer-related mutations—remains unclear. We hypothesized that CDK12 loss could induce malignant transformation of normal prostate cells, particularly in the setting of concurrent TP53 loss. Methods: To test the hypothesis, we generated mice with prostate-specific ablation of the CDK12 gene. We isolated prostate cells from these animals and used CRISPR to ablate p53 in vitro. Next, we implanted genetically modified cells (subcutaneous allograft) into immunodeficient mice and measured tumor growth. Note that since CDK12 and p53 share a chromosome, they cannot easily be ablated simultaneously in vivo. Results: Mice with prostate-specific CDK12 ablation did not develop large tumors, but did accumulate pre-cancerous prostate lesions with aging. Mouse prostate cells lacking either CDK12 or p53 alone did not form significant tumors in the allograft system. On the contrary, those lacking both CDK12 and p53 did form significant tumors. Conclusion: CDK12 loss alone is insufficient to cause prostate cancer in a mouse model; however, CDK12 inactivation enhances the effect of other cancer-associated mutations.
Biomedical Sciences, Interdisciplinary
