Abstract 4349: Characterization of a centrosome loss-induced tumorigenic signature in prostate epithelial cells
Authors: Jiawen Yang, Diogo de Oliveira Pessoa, John M. Ryniawec, Emily Loertscher, Anne E. Cress, Megha Padi, Gregory C. Rogers
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) stands as the second leading cause of cancer death in American men, with overtreatment being common given the difficulty in distinguishing between indolent and aggressive cases. Unlike many cancers, PCa lacks hallmark mutations in key oncogenes and tumor-suppressor genes. Instead, PCa exhibit extensive genomic rearrangements and chromosomal instability (CIN). CIN occurs during PCa progression, producing ETS gene family fusions, PTEN loss and androgen receptor amplification. Importantly, the mechanism underlying CIN in PCa remains unclear. Previously, we found that cell within early-grade human primary prostate adenocarcinomas (PRAD) frequently lack centrosomes, and this frequency correlates with tumor grade. We demonstrated that transient removal of centrosomes within non-tumorigenic human prostate epithelial cells (hPrEC) induces CIN and was, strikingly, sufficient to transform subpopulations of cells capable of producing xenograft tumors in mice. To unravel the molecular mechanisms underlying this path to tumorigenesis, we isolated DNA and RNA from parental hPrECs, clonal lines subjected to transient centrosome loss, and xenograft tumor cells and performed whole genome sequencing (WGS) and bulk RNA-seq. This allowed us to characterize the genomic profiles induced by centrosome loss and to identify an associated mutational signature. We used MUTECT2 to identify single nucleotide variants. Kataegis loci were observed on multiple chromosomes in all transient centrosome removal samples. Copy number variations were also detected in these samples using FACETS and SEQUENZA. Next, we extracted the copy number (CN) signature with SigProfiler and Sigminer, comparing it to COSMIC CN signatures and WGS data from PRAD patients. Our results revealed that the transient centrosome loss signature bears similarity to CN signatures associated with chromothripsis, loss of heterozygosity, and homologous recombination repair deficiency. Patients with PRAD displaying the centrosome loss CN signature had a poorer prognosis. Additionally, our CN analysis discovered that centrosome loss induced mosaic loss of chromosome Y in our samples. To detect structural variations, we employed DELLY, MANTA, SVABA, revealing a high occurrence of both non-clustered and clustered translocations in transient centrosome loss samples. These translocations were validated in our RNA-seq data using STAR-Fusion. Ongoing analyses include inferring CNV from PCa scRNA-seq data, and determining cell populations with the centrosome loss CN-signature and their associated transcriptome features. This work unveils a comprehensive genomic profile stemming from centrosome loss and demonstrates its role in driving oncogenesis in PCa. These findings have the potential to establish centrosome loss as a hallmark in PCa stratification, and lead to a significant advancement in prostate tumor treatment. Citation Format: Jiawen Yang, Diogo de Oliveira Pessoa, John M. Ryniawec, Emily Loertscher, Anne E. Cress, Megha Padi, Gregory C. Rogers. Characterization of a centrosome loss-induced tumorigenic signature in prostate epithelial cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4349.