182 results on '"Petrovics G"'
Search Results
2. Prostate cancer gene expression signature of patients with high body mass index
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Sharad, S, Srivastava, A, Ravulapalli, S, Parker, P, Chen, Y, Li, H, Petrovics, G, and Dobi, A
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- 2011
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3. Overexpression of C-MYC oncogene in prostate cancer predicts biochemical recurrence
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Hawksworth, D, Ravindranath, L, Chen, Y, Furusato, B, Sesterhenn, I A, McLeod, D G, Srivastava, S, and Petrovics, G
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- 2010
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4. Quantitative expression of TMPRSS2 transcript in prostate tumor cells reflects TMPRSS2–ERG fusion status
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Mwamukonda, K, Chen, Y, Ravindranath, L, Furusato, B, Hu, Y, Sterbis, J, Osborn, D, Rosner, I, Sesterhenn, I A, McLeod, D G, Srivastava, S, and Petrovics, G
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- 2010
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5. TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation
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Sun, C, Dobi, A, Mohamed, A, Li, H, Thangapazham, R L, Furusato, B, Shaheduzzaman, S, Tan, S-H, Vaidyanathan, G, Whitman, E, Hawksworth, D J, Chen, Y, Nau, M, Patel, V, Vahey, M, Gutkind, J S, Sreenath, T, Petrovics, G, Sesterhenn, I A, McLeod, D G, and Srivastava, S
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- 2008
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6. Transcriptome analyses of benign and malignant prostate epithelial cells in formalin-fixed paraffin-embedded whole-mounted radical prostatectomy specimens
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Furusato, B, Shaheduzzaman, S, Petrovics, G, Dobi, A, Seifert, M, Ravindranath, L, Nau, M E, Werner, T, Vahey, M, McLeod, D G, Srivastava, S, and Sesterhenn, I A
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- 2008
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7. Quantitative expression profile of PSGR in prostate cancer
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Xu, L L, Sun, C, Petrovics, G, Makarem, M, Furusato, B, Zhang, W, Sesterhenn, I A, McLeod, D G, Sun, L, Moul, J W, and Srivastava, S
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- 2006
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8. ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification
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Furusato, B, Tan, S-H, Young, D, Dobi, A, Sun, C, Mohamed, A A, Thangapazham, R, Chen, Y, McMaster, G, Sreenath, T, Petrovics, G, McLeod, D G, Srivastava, S, and Sesterhenn, I A
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- 2010
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9. Erratum: Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression
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DeRosa, C A, Furusato, B, Shaheduzzaman, S, Srikantan, V, Wang, Z, Chen, Y, Siefert, M, Ravindranath, L, Young, D, Nau, M, Dobi, A, Werner, T, McLeod, D G, Vahey, M T, Sesterhenn, I A, Srivastava, S, and Petrovics, G
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- 2012
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10. Erratum: Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome
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Petrovics, G, Liu, A, Shaheduzzaman, S, Furusato, B, Sun, C, Chen, Y, Nau, M, Ravindranath, L, Chen, Y, Dobi, A, Srikantan, V, Sesterhenn, I A, McLeod, D G, Vahey, M, Moul, J W, and Srivastava, S
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- 2007
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11. Induction of mucin gene expression in human colonic cell lines by PMA is dependent on PKC-[Epsilon]
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HONG, D.-H., PETROVICS, G., ANDERSON, W. B., FORSTNER, J., and FORSTNER, G.
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Gene expression -- Research ,Mucins -- Analysis ,Cells -- Analysis ,Intestines -- Physiological aspects ,Protein kinases -- Research ,Biological sciences - Abstract
Hong, D.-H., G. Petrovics, W. B. Anderson, J. Forstner, and G. Forstner. Induction of mucin gene expression in human colonic cell lines by PMA is dependent on PKC-[Epsilon]. Am. J. Physiol. 277 (Gastrointest. Liver Physiol. 40): G1041-G1047, 1999.--Treatment of HT-29 cells with phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), induces MUC2 expression. To investigate the role of PKC in regulating mucin genes in intestinal cells, we examined the regulation of MUC1, MUC2, MUC5AC, MUC5B, and MUC6 expression in two human mucin-producing colonic cell lines, T84 and HT29/A1. T84 and HT29/A1 cells (at 80-90% confluency) were exposed to 100 nM PMA for 0, 3, and 6 h. Twofold or greater increases in mRNA levels for MUC2 and MUC5AC were observed in both cell lines during this time period, whereas the levels of MUC1, MUC5B, and MUC6 mRNAs were only marginally affected. These results indicated that PKC differentially regulates mucin gene expression and that it may be responsible for altered mucin expression. Our previous results suggested that the [Ca.sup.2+]-independent PKC-[Epsilon] isoform appeared to mediate PMA-regulated mucin exocytosis in these cell lines. To determine if PKC-[Epsilon] was also involved in MUC2/MUC5AC gene induction, HT29/A1 cells were stably transfected with either a wild-type PKC-[Epsilon] or a dominant-negative ATP-binding mutant of PKC-[Epsilon] (PKC-[Epsilon] K437R). Overexpression of the dominant-negative PKC-[Epsilon] K437R blocked induction of both mucin genes, whereas PMA-induced mucin gene expression was not prevented by overexpression of wild-type PKC-[Epsilon]. PMA-dependent MUC2 mucin secretion was also blocked in cells overexpressing the dominant-negative PKC-[Epsilon] K437R. On the basis of these observations, PKC-[Epsilon] appears to mediate the expression of two major gastrointestinal mucins in response to PMA as well as PMA-regulated mucin exocytosis. protein kinase C; signal transduction; phorbol 12-myristate 13-acetate
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- 1999
12. Erratum: Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression
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DeRosa, C A, primary, Furusato, B, additional, Shaheduzzaman, S, additional, Srikantan, V, additional, Wang, Z, additional, Chen, Y, additional, Siefert, M, additional, Ravindranath, L, additional, Young, D, additional, Nau, M, additional, Dobi, A, additional, Werner, T, additional, McLeod, D G, additional, Vahey, M T, additional, Sesterhenn, I A, additional, Srivastava, S, additional, and Petrovics, G, additional
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- 2011
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13. Elevated osteonectin/SPARC expression in primary prostate cancer predicts metastatic progression
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DeRosa, C A, primary, Furusato, B, additional, Shaheduzzaman, S, additional, Srikantan, V, additional, Wang, Z, additional, Chen, Y, additional, Siefert, M, additional, Ravindranath, L, additional, Young, D, additional, Nau, M, additional, Dobi, A, additional, Werner, T, additional, McLeod, D G, additional, Vahey, M T, additional, Sesterhenn, I A, additional, Srivastava, S, additional, and Petrovics, G, additional
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- 2011
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14. Evaluation of PTEN and TMPRSS2-ERG abnormalities in prostate cancer by FISH and immunohistochemistry to address intra- and intertissue heterogeneity and disease progression.
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Joshua, A. M., primary, Evans, A., additional, Squire, J., additional, Yoshimoto, M., additional, Ludkovski, O., additional, Tan, S., additional, Dobi, A., additional, Furusato, B., additional, Petrovics, G., additional, Srivastava, S., additional, and Sesterhenn, I., additional
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- 2011
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15. ERG protein expression in prostate and vascular tumors: A potential for ERG-based stratification.
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Petrovics, G., primary, Tan, S., additional, Dobi, A., additional, Young, D., additional, Wang, Z., additional, Paetau, A., additional, Chen, Y., additional, Sreenath, T., additional, Brassell, S. A., additional, Miettinen, M., additional, Sesterhenn, I., additional, McLeod, D. G., additional, and Srivastava, S., additional
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- 2011
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16. Prostate cancer gene expression signature of patients with high body mass index
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Sharad, S, primary, Srivastava, A, additional, Ravulapalli, S, additional, Parker, P, additional, Chen, Y, additional, Li, H, additional, Petrovics, G, additional, and Dobi, A, additional
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- 2010
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17. UP-1.097: Osteoblast-Specific Factor 2 as a Putative High-Grade Tumor-Associated Stromal Marker for Prostate Cancer: Identification Through Microarray Technology
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Furusato, B., primary, Tsunoda, T., additional, Shaheduzzaman, S., additional, Nau, M., additional, Vahey, M., additional, Petrovics, G., additional, McLeod, D., additional, Naito, S., additional, Srivastava, S., additional, and Sesterhenn, I., additional
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- 2009
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18. MP-15.14: Elevated Secreted Protein, Acidic, and Rich in Cysteine (SPARC) Expression in Prostate Cancer Correlates with Tumor Metastasis after Radical Prostatectomy
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Furusato, B., primary, DeRosa, C., additional, Chen, Y., additional, Ravindranath, L., additional, Cook, C., additional, Cullen, J., additional, Petrovics, G., additional, Srivastava, S., additional, McLeod, D., additional, and Sesterhenn, I., additional
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- 2009
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19. Quantitative expression of TMPRSS2 transcript in prostate tumor cells reflects TMPRSS2–ERG fusion status
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Mwamukonda, K, primary, Chen, Y, additional, Ravindranath, L, additional, Furusato, B, additional, Hu, Y, additional, Sterbis, J, additional, Osborn, D, additional, Rosner, I, additional, Sesterhenn, I A, additional, McLeod, D G, additional, Srivastava, S, additional, and Petrovics, G, additional
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- 2009
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20. Transcriptome analyses of benign and malignant prostate epithelial cells in formalin-fixed paraffin-embedded whole-mounted radical prostatectomy specimens
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Furusato, B, primary, Shaheduzzaman, S, additional, Petrovics, G, additional, Dobi, A, additional, Seifert, M, additional, Ravindranath, L, additional, Nau, M E, additional, Werner, T, additional, Vahey, M, additional, McLeod, D G, additional, Srivastava, S, additional, and Sesterhenn, I A, additional
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- 2007
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21. Frequent Overexpression of ETS-Related Gene-1 (ERG1) in Prostate Cancer Transcriptome
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Petrovics, G., primary, Liu, A., additional, Shaheduzzaman, S., additional, Furasato, B., additional, Sun, C., additional, Chen, Y., additional, Nau, M., additional, Ravindranath, L., additional, Dobi, A., additional, Srikantan, V., additional, Sesterhenn, I.A., additional, McLeod, D.G., additional, Vahey, M., additional, Moul, J.W., additional, and Srivastava, S., additional
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- 2006
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22. Quantitative expression profile of PSGR in prostate cancer
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Xu, L L, primary, Sun, C, additional, Petrovics, G, additional, Makarem, M, additional, Furusato, B, additional, Zhang, W, additional, Sesterhenn, I A, additional, McLeod, D G, additional, Sun, L, additional, Moul, J W, additional, and Srivastava, S, additional
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- 2005
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23. Induction of mucin gene expression in human colonic cell lines by PMA is dependent on PKC-ε
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Hong, D.-H., primary, Petrovics, G., additional, Anderson, W. B., additional, Forstner, J., additional, and Forstner, G., additional
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- 1999
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24. The rkpGHI and -J genes are involved in capsular polysaccharide production by Rhizobium meliloti
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Kiss, E, primary, Reuhs, B L, additional, Kim, J S, additional, Kereszt, A, additional, Petrovics, G, additional, Putnoky, P, additional, Dusha, I, additional, Carlson, R W, additional, and Kondorosi, A, additional
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- 1997
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25. enod40, a gene expressed during nodule organogenesis, codes for a non-translatable RNA involved in plant growth.
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Crespi, M.D., primary, Jurkevitch, E., additional, Poiret, M., additional, d'Aubenton-Carafa, Y., additional, Petrovics, G., additional, Kondorosi, E., additional, and Kondorosi, A., additional
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- 1994
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26. Rhizobium meliloti lipopolysaccharide and exopolysaccharide can have the same function in the plant-bacterium interaction
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Putnoky, P, primary, Petrovics, G, additional, Kereszt, A, additional, Grosskopf, E, additional, Ha, D T, additional, Bánfalvi, Z, additional, and Kondorosi, A, additional
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- 1990
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27. Oxidative stress induces proorphanin FQ and proenkephalin gene expression in astrocytes through p38- and ERK-MAP kinases and NF-κB.
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Rosenberger, J., Petrovics, G., and Buzas, B.
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REACTIVE oxygen species , *NEUROPEPTIDES , *ASTROCYTES , *PROTEIN kinases - Abstract
Oxidative stress has been implicated in the pathogenesis of stroke, traumatic brain injuries, and neurodegenerative diseases affecting both neuronal and glial cells in the CNS. In this study we have demonstrated that reactive oxygen species (ROS) dramatically induce the expression of two neuropeptide genes, the opioid proenkephalin (pENK) and the opioid-related proorphanin FQ (pOFQ; also known as pronociceptin) in primary astrocytes. Hydrogen peroxide (H[sub 2]O[sub 2]) treatment dose-dependently increased pENK and pOFQ mRNA levels with a maximal effect (∼15-fold increase) being detected at 50 µm concentration. Exposing the astrocyte cultures to hypoxia and subsequent re-oxygenation also led to a profound elevation of pOFQ and pENK mRNA levels. Western blot analysis and immunocytochemistry revealed that H[sub 2]O[sub 2] treatment elicited the phosphorylation and nuclear translocation of ERK 1/2 and p38 MAP kinases. Blockade of the p38 or the ERK MAP kinase pathways (by SB202190 and PD98059, respectively) prevented the H[sub 2]O[sub 2]-induced increase in pENK and pOFQ mRNA levels indicating a central role for these cascades in the regulation of pOFQ and pENK genes in response to oxidative stress. Regulation of pOFQ and pENK gene expression by ERK and p38 activation may be mediated through the transcription factor cAMP-response element binding protein (CREB). We observed CREB phosphorylation in response to H[sub 2]O[sub 2], which was also prevented by SB202190 and PD98059. The nuclear factor-κB (NF-κB) pathway appears to be involved exclusively in the induction of pOFQ transcription by H[sub 2]O[sub 2], as NF-κB inhibitors antagonized the effect of oxidative stress on pOFQ, but not on pENK expression. The profound induction of these genes by oxidative stress and these other factors may suggest a role for orphanin FQ and enkephalin in injury and stress responses of the CNS and neuropathophysiological conditions involving reactive oxygen species. [ABSTRACT FROM AUTHOR]
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- 2001
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28. Up-regulation of the Pit-2 phosphate transporter/retrovirus receptor by protein kinase C epsilon.
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Jobbagy, Z, Olah, Z, Petrovics, G, Eiden, M V, Leverett, B D, Dean, N M, and Anderson, W B
- Abstract
The membrane receptors for the gibbon ape leukemia retrovirus and the amphotropic murine retrovirus serve normal cellular functions as sodium-dependent phosphate transporters (Pit-1 and Pit-2, respectively). Our earlier studies established that activation of protein kinase C (PKC) by treatment of cells with phorbol 12-myristate 13-acetate (PMA) enhanced sodium-dependent phosphate (Na/Pi) uptake. Studies now have been carried out to determine which type of Na/Pi transporter (Pit-1 or Pit-2) is regulated by PKC and which PKC isotypes are involved in the up-regulation of Na/Pi uptake by the Na/Pi transporter/viral receptor. It was found that the activation of short term (2-min) Na/Pi uptake by PMA is abolished when cells are infected with amphotropic murine retrovirus (binds Pit-2 receptor) but not with gibbon ape leukemia retrovirus (binds Pit-1 receptor), indicating that Pit-2 is the form of Na/Pi transporter/viral receptor regulated by PKC. The PKC-mediated activation of Pit-2 was blocked by pretreating cells with the pan-PKC inhibitor bisindolylmaleimide but not with the conventional PKC isotype inhibitor Gö 6976, suggesting that a novel PKC isotype is required to regulate Pit-2. Overexpression of PKCepsilon, but not of PKCalpha, -delta, or -zeta, was found to mimic the activation of Na/Pi uptake. To further establish that PKCepsilon is involved in the regulation of Pit-2, cells were treated with PKCepsilon-selective antisense oligonucleotides. Treatment with PKCepsilon antisense oligonucleotides decreased the PMA-induced activation of Na/Pi uptake. These results indicate that PMA-induced stimulation of Na/Pi uptake by Pit-2 is specifically mediated through activation of PKCepsilon.
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- 1999
29. Protein kinase C epsilon subcellular localization domains and proteolytic degradation sites. A model for protein kinase C conformational changes.
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Lehel, C, Oláh, Z, Jakab, G, Szállási, Z, Petrovics, G, Harta, G, Blumberg, P M, and Anderson, W B
- Abstract
Protein kinase C (PCK) epsilon has been found to have unique properties among the PCK isozymes in terms of its membrane association, oncogenic potential, and substrate specificity. Recently we have demonstrated that PKC epsilon localizes to the Golgi network via its zinc finger domain and that both the holoenzyme and its zinc finger region modulate Golgi function. To further characterize the relationship between the domain organization and the subcellular localization of PKC epsilon, a series of NIH 3T3 cell lines were created, each overexpressing a different truncated version of PKC epsilon. The overexpressed proteins each were designed to contain an epsilon-epitope tag peptide at the COOH terminus to allow ready detection with an antibody specific for the tag. The subcellular localization of the recombinant proteins was analyzed by in vivo phorbol ester binding, immunocytochemistry, and cell fractionation followed by immunoblotting. Results revealed several regions of PKC epsilon that contain putative subcellular localization signals. The presence either of the hinge region or of a 33-amino-acid region including the pseudosubstrate sequence in the recombinant proteins resulted in association with the plasma membrane and cytoskeletal components. The catalytic domain was found predominantly in the cytosolic fraction. The accessibility and thus the dominance of these localization signals is likely to be affected by the overall conformation of the recombinant proteins. Regions with putative proteolytic degradation sites also were identified. The susceptibility of the overexpressed proteins to proteolytic degradation was dependent on the protein conformation. Based on these observations, a model depicting the interaction and hierarchy of the suspected localization signals and proteolytic degradation sites is presented.
- Published
- 1995
30. Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome.
- Author
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Petrovics, G., Liu, A., Shaheduzzaman, S., Furusato, B., Sun, C., Chen, Y., Nau, M., Ravindranath, L., Dobi, A., Srikantan, V., Sesterhenn, I. A., McLeod, D. G., Vahey, M., Moul, J. W., and Srivastava, S.
- Subjects
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PROSTATE cancer - Abstract
A correction to the article "Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome" that was previously published in "Oncogene" is presented.
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- 2007
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31. Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression.
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Diossy M, Tisza V, Li H, Sahgal P, Zhou J, Sztupinszki Z, Young D, Nousome D, Kuo C, Jiang J, Chen Y, Ebner R, Sesterhenn IA, Moncur JT, Chesnut GT, Petrovics G, Klus GT, Valcz G, Nuzzo PV, Ribli D, Börcsök J, Prosz A, Krzystanek M, Ried T, Szuts D, Rizwan K, Kaochar S, Pathania S, D'Andrea AD, Csabai I, Srivastava S, Freedman ML, Dobi A, Spisak S, and Szallasi Z
- Abstract
We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men., (© 2024. The Author(s).)
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- 2024
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32. A selective CutMix approach improves generalizability of deep learning-based grading and risk assessment of prostate cancer.
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Patkar S, Harmon S, Sesterhenn I, Lis R, Merino M, Young D, Brown GT, Greenfield KM, McGeeney JD, Elsamanoudi S, Tan SH, Schafer C, Jiang J, Petrovics G, Dobi A, Rentas FJ, Pinto PA, Chesnut GT, Choyke P, Turkbey B, and Moncur JT
- Abstract
The Gleason score is an important predictor of prognosis in prostate cancer. However, its subjective nature can result in over- or under-grading. Our objective was to train an artificial intelligence (AI)-based algorithm to grade prostate cancer in specimens from patients who underwent radical prostatectomy (RP) and to assess the correlation of AI-estimated proportions of different Gleason patterns with biochemical recurrence-free survival (RFS), metastasis-free survival (MFS), and overall survival (OS). Training and validation of algorithms for cancer detection and grading were completed with three large datasets containing a total of 580 whole-mount prostate slides from 191 RP patients at two centers and 6218 annotated needle biopsy slides from the publicly available Prostate Cancer Grading Assessment dataset. A cancer detection model was trained using MobileNetV3 on 0.5 mm × 0.5 mm cancer areas (tiles) captured at 10× magnification. For cancer grading, a Gleason pattern detector was trained on tiles using a ResNet50 convolutional neural network and a selective CutMix training strategy involving a mixture of real and artificial examples. This strategy resulted in improved model generalizability in the test set compared with three different control experiments when evaluated on both needle biopsy slides and whole-mount prostate slides from different centers. In an additional test cohort of RP patients who were clinically followed over 30 years, quantitative Gleason pattern AI estimates achieved concordance indexes of 0.69, 0.72, and 0.64 for predicting RFS, MFS, and OS times, outperforming the control experiments and International Society of Urological Pathology system (ISUP) grading by pathologists. Finally, unsupervised clustering of test RP patient specimens into low-, medium-, and high-risk groups based on AI-estimated proportions of each Gleason pattern resulted in significantly improved RFS and MFS stratification compared with ISUP grading. In summary, deep learning-based quantitative Gleason scoring using a selective CutMix training strategy may improve prognostication after prostate cancer surgery., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2024
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33. Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression without inducing homologous recombination deficiency.
- Author
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Szallasi Z, Diossy M, Tisza V, Li H, Sahgal P, Zhou J, Sztupinszki Z, Young D, Nuosome D, Kuo C, Jiang J, Chen Y, Ebner R, Sesterhenn I, Moncur J, Chesnut G, Petrovics G, T Klus G, Valcz G, Nuzzo P, Ribli D, Börcsök J, Prósz A, Krzystanek M, Ried T, Szüts D, Rizwan K, Kaochar S, Pathania S, D'Andrea A, Csabai I, Srivastava S, Freedman M, Dobi A, and Spisak S
- Abstract
We analyzed genomic data derived from the prostate cancer of African and European American men in order to identify differences that may contribute to racial disparity of outcome and that could also define novel therapeutic strategies. In addition to analyzing patient derived next generation sequencing data, we performed FISH based confirmatory studies of Chromodomain helicase DNA-binding protein 1 ( CHD1 ) loss on prostate cancer tissue microarrays. We created CRISPR edited, CHD1 deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. We found that subclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of African American men than in men of European ancestry and it associates with rapid disease progression. We further showed that CHD1 deletion is not associated with homologous recombination deficiency associated mutational signatures in prostate cancer. In prostate cancer cell line models CHD1 deletion did not induce HR deficiency as detected by RAD51 foci formation assay or mutational signatures, which was consistent with the moderate increase of olaparib sensitivity. CHD1 deficient prostate cancer cells, however, showed higher sensitivity to talazoparib. CHD1 loss may contribute to worse outcome of prostate cancer in African American men. A deeper understanding of the interaction between CHD1 loss and PARP inhibitor sensitivity will be needed to determine the optimal use of targeted agents such as talazoparib in the context of castration resistant prostate cancer.
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- 2024
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34. Clinical Biofluid Assays for Prostate Cancer.
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Borbiev T, Kohaar I, and Petrovics G
- Abstract
This mini review summarizes the currently available clinical biofluid assays for PCa. The second most prevalent cancer worldwide is PCa. PCa is a heterogeneous disease, with a large percentage of prostate tumors being indolent, and with a relatively slow metastatic potential. However, due to the high case numbers, the absolute number of PCa-related deaths is still high. In fact, it causes the second highest number of cancer deaths in American men. As a first step for the diagnosis of PCa, the PSA test has been widely used. However, it has low specificity, which results in a high number of false positives leading to overdiagnosis and overtreatment. Newer derivatives of the original PSA test, including the Food and Drug Administration (FDA)-approved 4K (four kallikreins) and the PHI (Prostate Health Index) blood tests, have higher specificities. Tissue-based PCa tests are problematic as biopsies are invasive and have limited accuracy due to prostate tumor heterogeneity. Liquid biopsies offer a minimally or non-invasive choice for the patients, while providing a more representative reflection of the spatial heterogeneity in the prostate. In addition to the abovementioned blood-based tests, urine is a promising source of PCa biomarkers, offering a supplementary avenue for early detection and improved tumor classification. Four urine-based PCa tests are either FDA- or CLIA-approved: PCA3 (PROGENSA), ExoDX Prostate Intelliscore, MiPS, and SelectMDx. We will discuss these urine-based, as well as the blood-based, clinical PCa tests in more detail. We also briefly discuss a few promising biofluid marker candidates (DNA methylation, micro-RNAs) which are not in clinical application. As no single assay is perfect, we envision that a combination of biomarkers, together with imaging, will become the preferred practice.
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- 2023
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35. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.
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Wang A, Shen J, Rodriguez AA, Saunders EJ, Chen F, Janivara R, Darst BF, Sheng X, Xu Y, Chou AJ, Benlloch S, Dadaev T, Brook MN, Plym A, Sahimi A, Hoffman TJ, Takahashi A, Matsuda K, Momozawa Y, Fujita M, Laisk T, Figuerêdo J, Muir K, Ito S, Liu X, Uchio Y, Kubo M, Kamatani Y, Lophatananon A, Wan P, Andrews C, Lori A, Choudhury PP, Schleutker J, Tammela TLJ, Sipeky C, Auvinen A, Giles GG, Southey MC, MacInnis RJ, Cybulski C, Wokolorczyk D, Lubinski J, Rentsch CT, Cho K, Mcmahon BH, Neal DE, Donovan JL, Hamdy FC, Martin RM, Nordestgaard BG, Nielsen SF, Weischer M, Bojesen SE, Røder A, Stroomberg HV, Batra J, Chambers S, Horvath L, Clements JA, Tilly W, Risbridger GP, Gronberg H, Aly M, Szulkin R, Eklund M, Nordstrom T, Pashayan N, Dunning AM, Ghoussaini M, Travis RC, Key TJ, Riboli E, Park JY, Sellers TA, Lin HY, Albanes D, Weinstein S, Cook MB, Mucci LA, Giovannucci E, Lindstrom S, Kraft P, Hunter DJ, Penney KL, Turman C, Tangen CM, Goodman PJ, Thompson IM Jr, Hamilton RJ, Fleshner NE, Finelli A, Parent MÉ, Stanford JL, Ostrander EA, Koutros S, Beane Freeman LE, Stampfer M, Wolk A, Håkansson N, Andriole GL, Hoover RN, Machiela MJ, Sørensen KD, Borre M, Blot WJ, Zheng W, Yeboah ED, Mensah JE, Lu YJ, Zhang HW, Feng N, Mao X, Wu Y, Zhao SC, Sun Z, Thibodeau SN, McDonnell SK, Schaid DJ, West CML, Barnett G, Maier C, Schnoeller T, Luedeke M, Kibel AS, Drake BF, Cussenot O, Cancel-Tassin G, Menegaux F, Truong T, Koudou YA, John EM, Grindedal EM, Maehle L, Khaw KT, Ingles SA, Stern MC, Vega A, Gómez-Caamaño A, Fachal L, Rosenstein BS, Kerns SL, Ostrer H, Teixeira MR, Paulo P, Brandão A, Watya S, Lubwama A, Bensen JT, Butler EN, Mohler JL, Taylor JA, Kogevinas M, Dierssen-Sotos T, Castaño-Vinyals G, Cannon-Albright L, Teerlink CC, Huff CD, Pilie P, Yu Y, Bohlender RJ, Gu J, Strom SS, Multigner L, Blanchet P, Brureau L, Kaneva R, Slavov C, Mitev V, Leach RJ, Brenner H, Chen X, Holleczek B, Schöttker B, Klein EA, Hsing AW, Kittles RA, Murphy AB, Logothetis CJ, Kim J, Neuhausen SL, Steele L, Ding YC, Isaacs WB, Nemesure B, Hennis AJM, Carpten J, Pandha H, Michael A, De Ruyck K, De Meerleer G, Ost P, Xu J, Razack A, Lim J, Teo SH, Newcomb LF, Lin DW, Fowke JH, Neslund-Dudas CM, Rybicki BA, Gamulin M, Lessel D, Kulis T, Usmani N, Abraham A, Singhal S, Parliament M, Claessens F, Joniau S, Van den Broeck T, Gago-Dominguez M, Castelao JE, Martinez ME, Larkin S, Townsend PA, Aukim-Hastie C, Bush WS, Aldrich MC, Crawford DC, Srivastava S, Cullen J, Petrovics G, Casey G, Wang Y, Tettey Y, Lachance J, Tang W, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Yamoah K, Govindasami K, Chokkalingam AP, Keaton JM, Hellwege JN, Clark PE, Jalloh M, Gueye SM, Niang L, Ogunbiyi O, Shittu O, Amodu O, Adebiyi AO, Aisuodionoe-Shadrach OI, Ajibola HO, Jamda MA, Oluwole OP, Nwegbu M, Adusei B, Mante S, Darkwa-Abrahams A, Diop H, Gundell SM, Roobol MJ, Jenster G, van Schaik RHN, Hu JJ, Sanderson M, Kachuri L, Varma R, McKean-Cowdin R, Torres M, Preuss MH, Loos RJF, Zawistowski M, Zöllner S, Lu Z, Van Den Eeden SK, Easton DF, Ambs S, Edwards TL, Mägi R, Rebbeck TR, Fritsche L, Chanock SJ, Berndt SI, Wiklund F, Nakagawa H, Witte JS, Gaziano JM, Justice AC, Mancuso N, Terao C, Eeles RA, Kote-Jarai Z, Madduri RK, Conti DV, and Haiman CA
- Subjects
- Humans, Male, Black People genetics, Genome-Wide Association Study, Hispanic or Latino genetics, Polymorphism, Single Nucleotide, Risk Factors, White People genetics, Asian People genetics, Genetic Predisposition to Disease, Prostatic Neoplasms genetics
- Abstract
The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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36. Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.
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Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, Saunders EJ, Dadaev T, Brook MN, Hoffmann TJ, Muir K, Wan P, Le Marchand L, Wilkens L, Wang Y, Schleutker J, MacInnis RJ, Cybulski C, Neal DE, Nordestgaard BG, Nielsen SF, Batra J, Clements JA, Cancer BioResource AP, Grönberg H, Pashayan N, Travis RC, Park JY, Albanes D, Weinstein S, Mucci LA, Hunter DJ, Penney KL, Tangen CM, Hamilton RJ, Parent MÉ, Stanford JL, Koutros S, Wolk A, Sørensen KD, Blot WJ, Yeboah ED, Mensah JE, Lu YJ, Schaid DJ, Thibodeau SN, West CM, Maier C, Kibel AS, Cancel-Tassin G, Menegaux F, John EM, Grindedal EM, Khaw KT, Ingles SA, Vega A, Rosenstein BS, Teixeira MR, Kogevinas M, Cannon-Albright L, Huff C, Multigner L, Kaneva R, Leach RJ, Brenner H, Hsing AW, Kittles RA, Murphy AB, Logothetis CJ, Neuhausen SL, Isaacs WB, Nemesure B, Hennis AJ, Carpten J, Pandha H, De Ruyck K, Xu J, Razack A, Teo SH, Newcomb LF, Fowke JH, Neslund-Dudas C, Rybicki BA, Gamulin M, Usmani N, Claessens F, Gago-Dominguez M, Castelao JE, Townsend PA, Crawford DC, Petrovics G, Casey G, Roobol MJ, Hu JF, Berndt SI, Van Den Eeden SK, Easton DF, Chanock SJ, Cook MB, Wiklund F, Witte JS, Eeles RA, Kote-Jarai Z, Watya S, Gaziano JM, Justice AC, Conti DV, and Haiman CA
- Subjects
- Humans, Male, Black People genetics, Genome-Wide Association Study, Multifactorial Inheritance genetics, Risk Factors, White People genetics, Genetic Predisposition to Disease, Prostatic Neoplasms genetics
- Abstract
Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS
269 ). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping., Competing Interests: Declaration of interests The authors have no conflicts of interest to disclose., (Copyright © 2023 American Society of Human Genetics. All rights reserved.)- Published
- 2023
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37. Development and characterization of an ETV1 rabbit monoclonal antibody for the immunohistochemical detection of ETV1 expression in cancer tissue specimens.
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Schafer C, Young D, Singh H, Jayakrishnan R, Banerjee S, Song Y, Dobi A, Petrovics G, Srivastava S, Srivastava S, Sesterhenn IA, Chesnut GT, and Tan SH
- Subjects
- Male, Humans, DNA-Binding Proteins genetics, Antibodies, Monoclonal, Immunoblotting, Transcription Factors genetics, Transcription Factors metabolism, Prostatic Neoplasms diagnosis
- Abstract
Background: Aberrant ETV1 overexpression arising from gene rearrangements or mutations occur frequently in prostate cancer, round cell sarcomas, gastrointestinal stromal tumors, gliomas, and other malignancies. The absence of specific monoclonal antibodies (mAb) has limited its detection and our understanding of its oncogenic function., Methods: An ETV1 specific rabbit mAb (29E4) was raised using an immunogenic peptide. Key residues essential for its binding were probed by ELISA and its binding kinetics were measured by surface plasmon resonance imaging (SPRi). Its selective binding to ETV1 was assessed by immunoblots and immunofluorescence assays (IFA), and by both single and double-immuno-histochemistry (IHC) assays on prostate cancer tissue specimens., Results: Immunoblot results showed that the mAb is highly specific and lacked cross-reactivity with other ETS factors. A minimal epitope with two phenylalanine residues at its core was found to be required for effective mAb binding. SPRi measurements revealed an equilibrium dissociation constant in the picomolar range, confirming its high affinity. ETV1 (+) tumors were detected in prostate cancer tissue microarray cases evaluated. IHC staining of whole-mounted sections revealed glands with a mosaic staining pattern of cells that are partly ETV1 (+) and interspersed with ETV1 (-) cells. Duplex IHC, using ETV1 and ERG mAbs, detected collision tumors containing glands with distinct ETV1 (+) and ERG (+) cells., Conclusions: The selective detection of ETV1 by the 29E4 mAb in immunoblots, IFA, and IHC assays using human prostate tissue specimens reveals a potential utility for the diagnosis, the prognosis of prostate adenocarcinoma and other cancers, and the stratification of patients for treatment by ETV1 inhibitors., Competing Interests: Declaration of Competing Interest The contents of this publication are the sole responsibility of the author (s) and do not necessarily reflect the views, opinions, or policies of Uniformed Services University of the Health Sciences (USUHS), the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD) or the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2023
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38. Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.
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Chen F, Madduri RK, Rodriguez AA, Darst BF, Chou A, Sheng X, Wang A, Shen J, Saunders EJ, Rhie SK, Bensen JT, Ingles SA, Kittles RA, Strom SS, Rybicki BA, Nemesure B, Isaacs WB, Stanford JL, Zheng W, Sanderson M, John EM, Park JY, Xu J, Wang Y, Berndt SI, Huff CD, Yeboah ED, Tettey Y, Lachance J, Tang W, Rentsch CT, Cho K, Mcmahon BH, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Sellers TA, Yamoah K, Murphy AB, Crawford DC, Patel AV, Bush WS, Aldrich MC, Cussenot O, Petrovics G, Cullen J, Neslund-Dudas CM, Stern MC, Kote-Jarai Z, Govindasami K, Cook MB, Chokkalingam AP, Hsing AW, Goodman PJ, Hoffmann TJ, Drake BF, Hu JJ, Keaton JM, Hellwege JN, Clark PE, Jalloh M, Gueye SM, Niang L, Ogunbiyi O, Idowu MO, Popoola O, Adebiyi AO, Aisuodionoe-Shadrach OI, Ajibola HO, Jamda MA, Oluwole OP, Nwegbu M, Adusei B, Mante S, Darkwa-Abrahams A, Mensah JE, Diop H, Van Den Eeden SK, Blanchet P, Fowke JH, Casey G, Hennis AJ, Lubwama A, Thompson IM Jr, Leach R, Easton DF, Preuss MH, Loos RJ, Gundell SM, Wan P, Mohler JL, Fontham ET, Smith GJ, Taylor JA, Srivastava S, Eeles RA, Carpten JD, Kibel AS, Multigner L, Parent MÉ, Menegaux F, Cancel-Tassin G, Klein EA, Andrews C, Rebbeck TR, Brureau L, Ambs S, Edwards TL, Watya S, Chanock SJ, Witte JS, Blot WJ, Michael Gaziano J, Justice AC, Conti DV, and Haiman CA
- Subjects
- Male, Humans, Genome-Wide Association Study, Risk Factors, Black People genetics, Genetic Predisposition to Disease, Prostatic Neoplasms genetics, Prostatic Neoplasms epidemiology
- Abstract
Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility., Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry., Design, Setting, and Participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry., Outcome Measurements and Statistical Analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness., Results and Limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10
-4 )., Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry., Patient Summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)- Published
- 2023
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39. Association of TP53 Single Nucleotide Polymorphisms with Prostate Cancer in a Racially Diverse Cohort of Men.
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Duncan A, Nousome D, Ricks R, Kuo HC, Ravindranath L, Dobi A, Cullen J, Srivastava S, Chesnut GT, Petrovics G, and Kohaar I
- Abstract
Growing evidence indicates the involvement of a genetic component in prostate cancer (CaP) susceptibility and clinical severity. Studies have reported the role of germline mutations and single nucleotide polymorphisms (SNPs) of TP53 as possible risk factors for cancer development. In this single institutional retrospective study, we identified common SNPs in the TP53 gene in AA and CA men and performed association analyses for functional TP53 SNPs with the clinico-pathological features of CaP. The SNP genotyping analysis of the final cohort of 308 men (212 AA; 95 CA) identified 74 SNPs in the TP53 region, with a minor allele frequency (MAF) of at least 1%. Two SNPs were non-synonymous in the exonic region of TP53 : rs1800371 (Pro47Ser) and rs1042522 (Arg72Pro). The Pro47Ser variant had an MAF of 0.01 in AA but was not detected in CA. Arg72Pro was the most common SNP, with an MAF of 0.50 (0.41 in AA; 0.68 in CA). Arg72Pro was associated with a shorter time to biochemical recurrence (BCR) ( p = 0.046; HR = 1.52). The study demonstrated ancestral differences in the allele frequencies of the TP53 Arg72Pro and Pro47Ser SNPs, providing a valuable framework for evaluating CaP disparities among AA and CA men.
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- 2023
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40. Differentially expressed glycoproteins in pre- and post-digital rectal examination urine samples for detecting aggressive prostate cancer.
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Wang Y, Lih TM, Höti N, Sokoll LJ, Chesnut G, Petrovics G, Kohaar I, and Zhang H
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- Male, Humans, Prostate-Specific Antigen, Neoplasm Grading, Glycoproteins, Digital Rectal Examination, Prostatic Neoplasms diagnosis, Prostatic Neoplasms pathology
- Abstract
Urinary glycoproteins associated with aggressive prostate cancer (AG-PCa) were previously reported using post-digital rectal examination (DRE) urine specimens. To explore the potential of using pre-DRE urine specimens for detecting AG-PCa, we compared glycoproteins between pre- and post-DRE urine specimens, verified the previously identified post-DRE AG-PCa-associated urinary glycoproteins in pre-DRE urine specimens, and explored potential new glycoproteins for AG-PCa detection in pre-DRE urine specimens. Quantitative glycoproteomic data were acquired for 154 pre-DRE urine specimens from 41 patients with no cancer at biopsy, 48 patients with non-AG-PCa (Gleason score = 6), and 65 patients with AG-PCa (Gleason score 7 or above). Compared to glycopeptides from the post-DRE urine data, humoral immunity-related proteins were enriched in pre-DRE urine samples, whereas cell mediated immune response proteins were enriched in post-DRE urine samples. Analyses of AG-PCa-associated glycoproteins from pre-DRE urine revealed that the three urinary glycoproteins, prostate-specific antigen (PSA), prostatic acid phosphatase (ACPP), and CD97 antigen (CD97) that were previously identified in post-DRE urine samples, were also observed as AG-PCa associated glycoproteins in pre-DRE urine. In addition, we identified three new glycoproteins, fibrillin 1 (FBN1), vitronectin (VTN), and hemicentin 2 (HMCN2), to be potentially associated with AG-PCa in pre-DRE urine specimens. In summary, glycoprotein profiles differ between pre- and post-DRE urine specimens. The identified AG-PCa-associated glycoproteins may be further evaluated in large cohort of pre-DRE urine specimens for detecting clinically significant PCa., (© 2022 The Authors. Proteomics published by Wiley-VCH GmbH.)
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- 2023
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41. Biomarkers of Aggressive Prostate Cancer at Diagnosis.
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Boehm BE, York ME, Petrovics G, Kohaar I, and Chesnut GT
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- Male, Humans, United States, Prostate pathology, Prostate-Specific Antigen, Early Detection of Cancer, Biopsy, Biomarkers, Tumor metabolism, Prostatic Neoplasms diagnosis, Prostatic Neoplasms pathology
- Abstract
In the United States, prostate cancer (CaP) remains the second leading cause of cancer deaths in men. CaP is predominantly indolent at diagnosis, with a small fraction (25-30%) representing an aggressive subtype (Gleason score 7-10) that is prone to metastatic progression. This fact, coupled with the criticism surrounding the role of prostate specific antigen in prostate cancer screening, demonstrates the current need for a biomarker(s) that can identify clinically significant CaP and avoid unnecessary biopsy procedures and psychological implications of being diagnosed with low-risk prostate cancer. Although several diagnostic biomarkers are available to clinicians, very few comparative trials have been performed to assess the clinical effectiveness of these biomarkers. It is of note, however, that a majority of these clinical trials have been over-represented by men of Caucasian origin, despite the fact that African American men have a 1.7 times higher incidence and 2.1 times higher rate of mortality from prostate cancer. Biomarkers for CaP diagnosis based on the tissue of origin include urine-based gene expression assays (PCA3, Select MDx, ExoDx Prostate IntelliScore, Mi-Prostate Score, PCA3-PCGEM1 gene panel), blood-based protein biomarkers (4K, PHI), and tissue-based DNA biomarker (Confirm MDx). Another potential direction that has emerged to aid in the CaP diagnosis include multi-parametric magnetic resonance imaging (mpMRI) and bi-parametric magnetic resonance imaging (bpMRI), which in conjunction with clinically validated biomarkers may provide a better approach to predict clinically significant CaP at diagnosis. In this review, we discuss some of the adjunctive biomarker tests along with newer imaging modalities that are currently available to help clinicians decide which patients are at risk of having high-grade CaP on prostate biopsy with the emphasis on clinical utility of the tests across African American (AA) and Caucasian (CA) men.
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- 2023
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42. A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry.
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Darst BF, Hughley R, Pfennig A, Hazra U, Fan C, Wan P, Sheng X, Xia L, Andrews C, Chen F, Berndt SI, Kote-Jarai Z, Govindasami K, Bensen JT, Ingles SA, Rybicki BA, Nemesure B, John EM, Fowke JH, Huff CD, Strom SS, Isaacs WB, Park JY, Zheng W, Ostrander EA, Walsh PC, Carpten J, Sellers TA, Yamoah K, Murphy AB, Sanderson M, Crawford DC, Gapstur SM, Bush WS, Aldrich MC, Cussenot O, Petrovics G, Cullen J, Neslund-Dudas C, Kittles RA, Xu J, Stern MC, Chokkalingam AP, Multigner L, Parent ME, Menegaux F, Cancel-Tassin G, Kibel AS, Klein EA, Goodman PJ, Stanford JL, Drake BF, Hu JJ, Clark PE, Blanchet P, Casey G, Hennis AJM, Lubwama A, Thompson IM Jr, Leach RJ, Gundell SM, Pooler L, Mohler JL, Fontham ETH, Smith GJ, Taylor JA, Brureau L, Blot WJ, Biritwum R, Tay E, Truelove A, Niwa S, Tettey Y, Varma R, McKean-Cowdin R, Torres M, Jalloh M, Magueye Gueye S, Niang L, Ogunbiyi O, Oladimeji Idowu M, Popoola O, Adebiyi AO, Aisuodionoe-Shadrach OI, Nwegbu M, Adusei B, Mante S, Darkwa-Abrahams A, Yeboah ED, Mensah JE, Anthony Adjei A, Diop H, Cook MB, Chanock SJ, Watya S, Eeles RA, Chiang CWK, Lachance J, Rebbeck TR, Conti DV, and Haiman CA
- Subjects
- Case-Control Studies, Genetic Predisposition to Disease, Germ Cells pathology, Germ-Line Mutation, Homeodomain Proteins genetics, Humans, Male, Prostate-Specific Antigen genetics, Early Detection of Cancer, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
A rare African ancestry-specific germline deletion variant in HOXB13 (X285K, rs77179853) was recently reported in Martinican men with early-onset prostate cancer. Given the role of HOXB13 germline variation in prostate cancer, we investigated the association between HOXB13 X285K and prostate cancer risk in a large sample of 22 361 African ancestry men, including 11 688 prostate cancer cases. The risk allele was present only in men of West African ancestry, with an allele frequency in men that ranged from 0.40% in Ghana and 0.31% in Nigeria to 0% in Uganda and South Africa, with a range of frequencies in men with admixed African ancestry from North America and Europe (0-0.26%). HOXB13 X285K was associated with 2.4-fold increased odds of prostate cancer (95% confidence interval [CI] = 1.5-3.9, p = 2 × 10
-4 ), with greater risk observed for more aggressive and advanced disease (Gleason ≥8: odds ratio [OR] = 4.7, 95% CI = 2.3-9.5, p = 2 × 10-5 ; stage T3/T4: OR = 4.5, 95% CI = 2.0-10.0, p = 2 × 10-4 ; metastatic disease: OR = 5.1, 95% CI = 1.9-13.7, p = 0.001). We estimated that the allele arose in West Africa 1500-4600 yr ago. Further analysis is needed to understand how the HOXB13 X285K variant impacts the HOXB13 protein and function in the prostate. Understanding who carries this mutation may inform prostate cancer screening in men of West African ancestry. PATIENT SUMMARY: A rare African ancestry-specific germline deletion in HOXB13, found only in men of West African ancestry, was reported to be associated with an increased risk of overall and advanced prostate cancer. Understanding who carries this mutation may help inform screening for prostate cancer in men of West African ancestry., (Copyright © 2022. Published by Elsevier B.V.)- Published
- 2022
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43. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score.
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Huynh-Le MP, Karunamuni R, Fan CC, Asona L, Thompson WK, Martinez ME, Eeles RA, Kote-Jarai Z, Muir KR, Lophatananon A, Schleutker J, Pashayan N, Batra J, Grönberg H, Neal DE, Nordestgaard BG, Tangen CM, MacInnis RJ, Wolk A, Albanes D, Haiman CA, Travis RC, Blot WJ, Stanford JL, Mucci LA, West CML, Nielsen SF, Kibel AS, Cussenot O, Berndt SI, Koutros S, Sørensen KD, Cybulski C, Grindedal EM, Menegaux F, Park JY, Ingles SA, Maier C, Hamilton RJ, Rosenstein BS, Lu YJ, Watya S, Vega A, Kogevinas M, Wiklund F, Penney KL, Huff CD, Teixeira MR, Multigner L, Leach RJ, Brenner H, John EM, Kaneva R, Logothetis CJ, Neuhausen SL, De Ruyck K, Ost P, Razack A, Newcomb LF, Fowke JH, Gamulin M, Abraham A, Claessens F, Castelao JE, Townsend PA, Crawford DC, Petrovics G, van Schaik RHN, Parent MÉ, Hu JJ, Zheng W, Mills IG, Andreassen OA, Dale AM, and Seibert TM
- Subjects
- Male, Humans, Early Detection of Cancer, Polymorphism, Single Nucleotide, Risk Factors, Risk Assessment, Genetic Predisposition to Disease, Prostate-Specific Antigen genetics, Prostatic Neoplasms diagnosis, Prostatic Neoplasms genetics
- Abstract
Background: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets., Methods: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured., Results: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively., Conclusions: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations., (© 2022. The Author(s).)
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- 2022
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44. Focal p53 protein expression and lymphovascular invasion in primary prostate tumors predict metastatic progression.
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Gesztes W, Schafer C, Young D, Fox J, Jiang J, Chen Y, Kuo HC, Mwamukonda KB, Dobi A, Burke AP, Moul JW, McLeod DG, Rosner IL, Petrovics G, Tan SH, Cullen J, Srivastava S, and Sesterhenn IA
- Subjects
- Humans, Immunohistochemistry, Male, Prognosis, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Prostate pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Prostatic Neoplasms surgery
- Abstract
TP53 is one of the most frequently altered genes in prostate cancer. The precise assessment of its focal alterations in primary tumors by immunohistochemistry (IHC) has significantly enhanced its prognosis. p53 protein expression and lymphovascular invasion (LVI) were evaluated for predicting metastatic progression by IHC staining of representative whole-mounted prostate sections from a cohort of 189 radical prostatectomy patients with up to 20 years of clinical follow-up. Kaplan-Meier survival curves were used to examine time to distant metastasis (DM) as a function of p53 expression and LVI status. TP53 targeted sequencing was performed in ten tumors with the highest expression of p53 staining. Nearly half (49.8%) of prostate tumors examined showed focal p53 expression while 26.6% showed evidence of LVI. p53(+) tumors had higher pathologic T stage, Grade Group, Nuclear Grade, and more frequent LVI. p53 expression of > 5% and LVI, individually and jointly, are associated with poorer DM-free survival. TP53 mutations were detected in seven of ten tumors sequenced. Four tumors with the highest p53 expression harbored likely pathogenic or pathogenic mutations. High levels of p53 expression suggest the likelihood of pathogenic TP53 alterations and, together with LVI status, could enhance early prognostication of prostate cancer progression., (© 2022. The Author(s).)
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- 2022
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45. Germline mutation landscape of DNA damage repair genes in African Americans with prostate cancer highlights potentially targetable RAD genes.
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Kohaar I, Zhang X, Tan SH, Nousome D, Babcock K, Ravindranath L, Sukumar G, Mcgrath-Martinez E, Rosenberger J, Alba C, Ali A, Young D, Chen Y, Cullen J, Rosner IL, Sesterhenn IA, Dobi A, Chesnut G, Turner C, Dalgard C, Wilkerson MD, Pollard HB, Srivastava S, and Petrovics G
- Subjects
- DNA Damage genetics, Germ-Line Mutation, Humans, Male, Mutation, Black or African American genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2022
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46. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.
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Karunamuni RA, Huynh-Le MP, Fan CC, Thompson W, Lui A, Martinez ME, Rose BS, Mahal B, Eeles RA, Kote-Jarai Z, Muir K, Lophatananon A, Tangen CM, Goodman PJ, Thompson IM Jr, Blot WJ, Zheng W, Kibel AS, Drake BF, Cussenot O, Cancel-Tassin G, Menegaux F, Truong T, Park JY, Lin HY, Taylor JA, Bensen JT, Mohler JL, Fontham ETH, Multigner L, Blanchet P, Brureau L, Romana M, Leach RJ, John EM, Fowke JH, Bush WS, Aldrich MC, Crawford DC, Cullen J, Petrovics G, Parent MÉ, Hu JJ, Sanderson M, Mills IG, Andreassen OA, Dale AM, and Seibert TM
- Subjects
- Case-Control Studies, Humans, Male, Polymorphism, Single Nucleotide, Risk Assessment, White People genetics, Black People genetics, Chromosomes, Human, Pair 8 genetics, Genetic Predisposition to Disease, Multifactorial Inheritance, Prostatic Neoplasms ethnology, Prostatic Neoplasms genetics
- Abstract
Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ., Materials and Methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC., Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings., Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2022
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47. Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.
- Author
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Conti DV, Darst BF, Moss LC, Saunders EJ, Sheng X, Chou A, Schumacher FR, Olama AAA, Benlloch S, Dadaev T, Brook MN, Sahimi A, Hoffmann TJ, Takahashi A, Matsuda K, Momozawa Y, Fujita M, Muir K, Lophatananon A, Wan P, Le Marchand L, Wilkens LR, Stevens VL, Gapstur SM, Carter BD, Schleutker J, Tammela TLJ, Sipeky C, Auvinen A, Giles GG, Southey MC, MacInnis RJ, Cybulski C, Wokołorczyk D, Lubiński J, Neal DE, Donovan JL, Hamdy FC, Martin RM, Nordestgaard BG, Nielsen SF, Weischer M, Bojesen SE, Røder MA, Iversen P, Batra J, Chambers S, Moya L, Horvath L, Clements JA, Tilley W, Risbridger GP, Gronberg H, Aly M, Szulkin R, Eklund M, Nordström T, Pashayan N, Dunning AM, Ghoussaini M, Travis RC, Key TJ, Riboli E, Park JY, Sellers TA, Lin HY, Albanes D, Weinstein SJ, Mucci LA, Giovannucci E, Lindstrom S, Kraft P, Hunter DJ, Penney KL, Turman C, Tangen CM, Goodman PJ, Thompson IM Jr, Hamilton RJ, Fleshner NE, Finelli A, Parent MÉ, Stanford JL, Ostrander EA, Geybels MS, Koutros S, Freeman LEB, Stampfer M, Wolk A, Håkansson N, Andriole GL, Hoover RN, Machiela MJ, Sørensen KD, Borre M, Blot WJ, Zheng W, Yeboah ED, Mensah JE, Lu YJ, Zhang HW, Feng N, Mao X, Wu Y, Zhao SC, Sun Z, Thibodeau SN, McDonnell SK, Schaid DJ, West CML, Burnet N, Barnett G, Maier C, Schnoeller T, Luedeke M, Kibel AS, Drake BF, Cussenot O, Cancel-Tassin G, Menegaux F, Truong T, Koudou YA, John EM, Grindedal EM, Maehle L, Khaw KT, Ingles SA, Stern MC, Vega A, Gómez-Caamaño A, Fachal L, Rosenstein BS, Kerns SL, Ostrer H, Teixeira MR, Paulo P, Brandão A, Watya S, Lubwama A, Bensen JT, Fontham ETH, Mohler J, Taylor JA, Kogevinas M, Llorca J, Castaño-Vinyals G, Cannon-Albright L, Teerlink CC, Huff CD, Strom SS, Multigner L, Blanchet P, Brureau L, Kaneva R, Slavov C, Mitev V, Leach RJ, Weaver B, Brenner H, Cuk K, Holleczek B, Saum KU, Klein EA, Hsing AW, Kittles RA, Murphy AB, Logothetis CJ, Kim J, Neuhausen SL, Steele L, Ding YC, Isaacs WB, Nemesure B, Hennis AJM, Carpten J, Pandha H, Michael A, De Ruyck K, De Meerleer G, Ost P, Xu J, Razack A, Lim J, Teo SH, Newcomb LF, Lin DW, Fowke JH, Neslund-Dudas C, Rybicki BA, Gamulin M, Lessel D, Kulis T, Usmani N, Singhal S, Parliament M, Claessens F, Joniau S, Van den Broeck T, Gago-Dominguez M, Castelao JE, Martinez ME, Larkin S, Townsend PA, Aukim-Hastie C, Bush WS, Aldrich MC, Crawford DC, Srivastava S, Cullen JC, Petrovics G, Casey G, Roobol MJ, Jenster G, van Schaik RHN, Hu JJ, Sanderson M, Varma R, McKean-Cowdin R, Torres M, Mancuso N, Berndt SI, Van Den Eeden SK, Easton DF, Chanock SJ, Cook MB, Wiklund F, Nakagawa H, Witte JS, Eeles RA, Kote-Jarai Z, and Haiman CA
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- 2021
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48. A Urine Exosome Gene Expression Panel Distinguishes between Indolent and Aggressive Prostate Cancers at Biopsy.
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Kohaar I, Chen Y, Banerjee S, Borbiev T, Kuo HC, Ali A, Ravindranath L, Kagan J, Srivastava S, Dobi A, Sesterhenn IA, Rosner IL, Cullen J, Srivastava S, and Petrovics G
- Subjects
- Adult, Aged, Aged, 80 and over, Biopsy, Cohort Studies, Diagnosis, Differential, Humans, Male, Middle Aged, Prostatic Neoplasms urine, Exosomes genetics, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology
- Abstract
Purpose: Prostate cancer is predominantly indolent at diagnosis with a small fraction (15% to 25%) representing aggressive subtype (Gleason score 7-10), which is prone to metastatic progression. It is critical to explore noninvasive assays for the early detection of this aggressive subtype, when it still can be treated effectively. Additionally, there is an emerging need to develop markers that perform equally well across races, as racial differences in the prevalence and mortality of prostate cancer has become evident., Materials and Methods: First catch, nondigital rectal examination urine specimens were collected from patients undergoing diagnostic biopsy. Total RNA was extracted from urinary exosomes and a quantitative expression assay protocol using droplet digital polymerase chain reaction was developed for detection of candidate genes in exosomal mRNAs from urine. Clinical performance for the gene expression assay was evaluated to predict high grade cancer (Gleason score 7-10) from low grade cancer (Gleason score 6) and cancer negative cases at biopsy. Assay performance was examined in combination with standard of care to determine improvement in model prediction., Results: In a racially diverse patient cohort a 2-gene panel ( PCA3, PCGEM1 ), in combination with standard of care variables, significantly improved the prediction of high grade cancer at diagnosis compared to standard of care variables alone (AUC 0.88 vs 0.80, respectively, p=0.016). Decision curve analysis showed that there is a benefit of adopting the gene panel for detection of high grade cancer compared to standard of care alone., Conclusions: This study highlights the potential for developing broadly applicable prostate cancer diagnostic biomarker panels for aggressive prostate cancer using our novel gene expression assay platform.
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- 2021
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49. Prognostic features of Annexin A2 expression in prostate cancer.
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Tan SH, Young D, Chen Y, Kuo HC, Srinivasan A, Dobi A, Petrovics G, Cullen J, Mcleod DG, Rosner IL, Srivastava S, and Sesterhenn IA
- Subjects
- Biomarkers, Tumor analysis, Biomarkers, Tumor metabolism, Disease Progression, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Grading, Neoplasm Staging, Prostate pathology, Transcriptional Regulator ERG analysis, Transcriptional Regulator ERG metabolism, Annexin A2 analysis, Annexin A2 metabolism, Prognosis, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology
- Abstract
ANXA2 (Annexin A2 or Annexin II) is a calcium dependent phospholipid binding protein with diverse cellular functions. While ANXA2 is either absent or expressed focally in the prostate epithelium of well and moderately differentiated tumours, it is highly expressed in a subset of poorly differentiated tumours. Here we examined the association between ANXA2 expression and tumour progression, with consideration of ERG expression status and patient race (Caucasian American and African American). We evaluated ANXA2 and ERG expression in index tumours by immunohistochemistry of whole mounted prostate sections and tissue microarrays derived from radical prostatectomies of 176 patients, matched for long term post-radical prostatectomy follow-up of up to 22 years (median 12.6 years), race and pathological stage. Expression of ERG and ANXA2 was analysed for correlation with grade group (GG), and pathological T (pT) stage. Kaplan-Meier estimation curves were used to examine associations between ANXA2 or ERG expression and biochemical recurrence (BCR) free survival, and distant metastasis free survival. Significant associations were found between ANXA2(+) index tumours and poorest grade groups (GG 4-5, p=0.0037), and worse pathological stage (pT 3-4, p=0.0142). Patients with ANXA2(+) prostate tumours showed trends towards earlier BCR and metastatic progression. ANXA2(+)/ERG(-) tumours were found to be associated with GG 4-5; ANXA2(-)/ERG(+) tumours, with GG 1-2 (p=0.0036). ANXA2 expression was not associated with patient race. The association between high ANXA2 expression and prostate tumours of higher grade (GG 4-5) and stage (pT 3-4) suggests a potential use for ANXA2 as a prognostic biomarker of aggressive prostate cancer., (Copyright © 2020 Royal College of Pathologists of Australasia. All rights reserved.)
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- 2021
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50. African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.
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Karunamuni RA, Huynh-Le MP, Fan CC, Thompson W, Eeles RA, Kote-Jarai Z, Muir K, Lophatananon A, Tangen CM, Goodman PJ, Thompson IM Jr, Blot WJ, Zheng W, Kibel AS, Drake BF, Cussenot O, Cancel-Tassin G, Menegaux F, Truong T, Park JY, Lin HY, Bensen JT, Fontham ETH, Mohler JL, Taylor JA, Multigner L, Blanchet P, Brureau L, Romana M, Leach RJ, John EM, Fowke J, Bush WS, Aldrich M, Crawford DC, Srivastava S, Cullen JC, Petrovics G, Parent MÉ, Hu JJ, Sanderson M, Mills IG, Andreassen OA, Dale AM, and Seibert TM
- Subjects
- Age Factors, Black People genetics, Case-Control Studies, Genotyping Techniques, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prostatic Neoplasms genetics, Black People statistics & numerical data, Genetic Predisposition to Disease, Models, Genetic, Multifactorial Inheritance, Prostatic Neoplasms epidemiology
- Abstract
Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans., (© 2020 Union for International Cancer Control.)
- Published
- 2021
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