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Pd05-05 a Transcriptomic Signature of Tertiary Gleason 5 Predicts Worse Clinicopathological Outcome

Year: 2019

Type: article

Abstract: You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (PD05)1 Apr 2019PD05-05 A TRANSCRIPTOMIC SIGNATURE OF TERTIARY GLEASON 5 PREDICTS WORSE CLINICOPATHOLOGICAL OUTCOME Alberto Martini, Joanna Wang, Nicholas Brown, Shivaram Cumarasamy*, Eithan Wajswol, John P Sfakianos, Ardeshir R Rastinehad, Kenneth G Haines, N Peter Wiklund, Sujit S Nair, and Ashutosh K Tewari Alberto MartiniAlberto Martini More articles by this author , Joanna WangJoanna Wang More articles by this author , Nicholas BrownNicholas Brown More articles by this author , Shivaram Cumarasamy*Shivaram Cumarasamy* More articles by this author , Eithan WajswolEithan Wajswol More articles by this author , John P SfakianosJohn P Sfakianos More articles by this author , Ardeshir R RastinehadArdeshir R Rastinehad More articles by this author , Kenneth G HainesKenneth G Haines More articles by this author , N Peter WiklundN Peter Wiklund More articles by this author , Sujit S NairSujit S Nair More articles by this author , and Ashutosh K TewariAshutosh K Tewari More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000555065.89092.0eAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: The presence of tertiary pattern 5 (TP5) on radical prostatectomy specimens has been associated with worse long-term outcomes. However, the molecular underpinnings of TP5 is poorly understood. We hypothesized that a comparative analysis of transcript profiles between Gleason matched tumors with and without TP5 would provide us a unique opportunity to identify genes that contribute to TP5 and investigated if genomic features of TP5 could explain the poor clinical outcomes associated with this disease subtype. METHODS: Data from 159 men who underwent radical prostatectomy and had Gleason Grade Group (GGG) 3 or 4 without primary or secondary pattern 5 on final pathology were considered. All patients had Decipher diagnostic test (assesses 5-year risk of metastasis post-RP). Additionally, transcript profiles and SCAN-normalized expression of coding genes were available for all 159 patients. The relationship between Decipher score and the presence of TP5 was investigated by means of linear and binary logistic regression. A differential transcriptomic analysis between patients with and without TP5 was performed in order to identify the genes associated with TP5 as a proxy of early dedifferentiation. The prognostic role of these genes in identifying patients with worse progression-free survival (PFS) and overall survival (OS) was then evaluated by utilizing The Cancer Genome Atlas provisional (TCGAp) accessed through the cBioPortal for Cancer Genomics. RESULTS: Overall, 52/159 (33%) patients had GGG 3-4 disease with TP5 while 107/159 (67%) harbored GGG 3-4 disease alone. The presence of TP5 was associated with a higher Decipher score (B: 0.07, 95% CI: 0.02, 0.13, p=0.04) and a higher likelihood of falling within the intermediate- or high-risk categories (OR: 3.34, 95% CI: 1.34, 8.35, p=0.01) rather than the low-risk category. Analysis of microarray data revealed an 18 gene signature that was differentially expressed in patients with TP5. Genes CDKN2B, CHIT1, PDSS1, CDK4, SRD5A1, CXCR6, DCK, PLK1, CDC20, FGF14, FLRT2, RARA, and CXXC5 were over-expressed in the TP5 cohort.A systematic analysis of genes in the TCGAp revealed that overexpression of CDKN2B, PLK1, and CDC20 was associated with worse PFS. When combined, the group harboring overexpression of at least one of these genes had a 5-year PFS rate of 50% versus 74% in the group without overexpression, p<0.001. CONCLUSIONS: Our study has elucidated unique genomic features of TP5 while confirming previous findings that patients harboring TP5 tend to have worse prognosis. Analysis of transcript profiles revealed that the expression levels of 18 genes were significantly altered in TP5 positive versus negative specimens. Furthermore, there is evidence that alterations in the expression levels of cell cycle genes CDKN2B, PLK1, and CDC20 are critical drivers of TP5. Analysis of independent prostate cancer datasets demonstrated that the overexpression of all three genes was associated with worse PFS. To the best of our knowledge, this is the first RNA-based study to investigate the molecular diversity of TP5 and the first one correlating CKDN2B to poorer prognosis in patients with prostate cancer. Source of Funding: None New York, NY© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e81-e82 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alberto Martini More articles by this author Joanna Wang More articles by this author Nicholas Brown More articles by this author Shivaram Cumarasamy* More articles by this author Eithan Wajswol More articles by this author John P Sfakianos More articles by this author Ardeshir R Rastinehad More articles by this author Kenneth G Haines More articles by this author N Peter Wiklund More articles by this author Sujit S Nair More articles by this author Ashutosh K Tewari More articles by this author Expand All Advertisement PDF downloadLoading ...

Source: The Journal of Urology

DOI: 10.1097/01.ju.0000555065.89092.0e