Abstract B058: Genetic contribution of MYC to the development of primary prostate cancer

Abstract

Abstract Introduction: The single best predictor of prostate cancer (PCa) outcome is Gleason score (Gs); however, the molecular characteristics that underpin specific Gleason patterns (Gp) and the biology associated with the aggressiveness of higher grades remain understudied. In a series of Gs 7 cancers, we recently observed increased activation of MYC and increased MYC protein levels in Gp4 prostate foci as compared to adjacent Gp3. While MYC is often associated with proliferative potential in other cancer types, subsets of prostate cancers show dramatically elevated MYC levels despite no increase in proliferation. These data suggest that increased MYC activity may drive Gp3 progression to Gp4 in a subset of cancers. Thus, the objective of this study is to examine the genetic contribution of MYC to locally advanced PCa development. Approach: To test the hypothesis that increased MYC activity drives the progression of Gp3 to Gp4 in a subset of cases, we screened a new series of Gs7 tumors in which the Gp3 and Gp4 components are adjacent and represent contributing elements of the index lesion. Guided by anti-MYC immunohistochemistry, tumor foci were collected by laser capture microdissection based on MYC staining, focusing in particular where MYC staining was markedly increased in Gp4 versus Gp3. We then copurified DNA and RNA; whole-exome sequencing and transcriptome profiling were performed. To further guide our bioinformatic analyses, we separately generated two prostate cell culture models with altered MYC levels: RWPE-1 cells to overexpress MYC and LNCAP cells to knockdown MYC. Total RNA was extracted and whole-transcriptome sequencing was used to assess differential gene expression. Results: Preliminary results from our first case suggest distinct histology and biology based on MYC tumor status from whole-exome sequencing analyses. Using somatic mutations and somatic copy number alterations, we observed a clonal relationship between two MYC-positive foci: a region of intraductal carcinoma and MYC-positive Gp4 adenocarcinoma. These regions shared identical single copy arm-level losses in chromosomes 6q and 8p, single-copy arm-level gains of 8q, 9p, and 9q, and 14 high-confidence point mutations that were not observed in the MYC-negative Gp3 component, suggesting that MYC activation may have driven evolution of the Gp4 component. When we cross-referenced differentially expressed genes between the Gp3 and Gp4 foci with our engineered cell lines and performed gene set enrichment analysis, we found recurrent enrichment for a JAK2 gene set, correlating with MYC activity. Conclusions: Our results demonstrate the feasibility of performing laser capture microdissection and integrated genomic analyses on tissue with differential MYC status. Although further cases are needed to determine the frequency at which JAK/STAT signaling drives MYC-driven prostate cancer, our improved understanding of its biology may lend itself to new strategies for managing newly diagnosed patients or delaying disease progression. Citation Format: Nichelle C. Whitlock, Rayann Atway, Qi Yang, Huihui Ye, Adam Sowalsky. Genetic contribution of MYC to the development of primary prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B058.