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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
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Low Expression of the Androgen-Induced Tumor Suppressor Gene PLZF and Lethal Prostate Cancer

Konrad H. Stopsack, Travis Gerke, Svitlana Tyekucheva, Ying Z. Mazzu, Gwo-Shu Mary Lee, Goutam Chakraborty, Wassim Abida, Lorelei A. Mucci and Philip W. Kantoff
Konrad H. Stopsack
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Konrad H. Stopsack
Travis Gerke
2Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
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Svitlana Tyekucheva
3Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
4Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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  • ORCID record for Svitlana Tyekucheva
Ying Z. Mazzu
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Gwo-Shu Mary Lee
5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Goutam Chakraborty
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Wassim Abida
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Lorelei A. Mucci
6Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
7Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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Philip W. Kantoff
1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: kantoff@mskcc.org
DOI: 10.1158/1055-9965.EPI-18-1014 Published April 2019
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    Figure 1.

    Regulators of PLZF mRNA expression. A, PLZF copy number and PLZF mRNA expression in TCGA (n = 333). B, Androgen receptor signature and PLZF mRNA expression in HPFS and PHS combined (n = 404). C, PTEN copy number and PLZF mRNA expression in TCGA (n = 333). D, PTEN by IHC and PLZF mRNA expression in HPFS and PHS (n = 260). A–E, Horizontal lines indicate the medians; boxes reach from the first to the third quartiles; and whiskers extend 1.5 times the interquartile range. Regulators of PLZF expression in multivariable models in the TCGA primary prostate cancer cohort (E) and in HPFS and PHS combined (F). All units of tumor PLZF expression are standard deviations.

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    Figure 2.

    Downstream consequences of low PLZF in HPFS and PHS. A, PLZF mRNA expression and a signature of MAPK signaling (n = 404). Horizontal lines indicate the medians; boxes reach from the first to the third quartiles; and whiskers extend 1.5 times the interquartile range. B, PLZF mRNA expression and risk of lethal disease over long-term follow-up in a multivariable model adjusting for patient, histologic, and genomic covariates.

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    Figure 3.

    Schematic overview of PLZF regulation and downstream consequences.

Tables

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  • Table 1.

    Baseline characteristics at cancer diagnosis of men with prostate cancer and tumor transcriptome profiling in TCGA, HPFS, and PHS, by PLZF mRNA expression (low: first quartile; normal: all higher quartiles)

    TCGAHPFSPHS
    PLZF expressionaLowNormalLowNormalLowNormal
    n842496818633117
    Age, median (range)64 (46–74)61 (43–76)65 (47–76)66 (49–80)65 (55–79)66 (51–81)
    Gleason score in grade groups, n (%)
     5–69 (11)56 (22)4 (6)20 (11)3 (9)30 (26)
     3+430 (36)72 (29)20 (29)71 (38)11 (33)37 (32)
     4+323 (27)55 (22)22 (32)52 (28)10 (30)18 (15)
     810 (12)35 (14)8 (12)13 (7)5 (15)17 (15)
     9–1012 (14)31 (12)14 (21)30 (16)4 (12)15 (13)
    Clinical stage, n (%)
     T1/T284 (100)249 (100)56 (85)158 (86)29 (88)107 (93)
     T3——5 (8)16 (9)3 (9)3 (3)
     T4/N1/M1——5 (8)9 (5)1 (3)5 (4)
    PSA,b n (%)
     <47 (15)12 (9)7 (12)17 (11)5 (19)12 (12)
     4–1030 (65)78 (55)27 (47)90 (58)15 (58)64 (62)
     10–207 (15)30 (21)13 (22)30 (19)3 (12)17 (17)
     >202 (4)21 (15)11 (19)17 (11)3 (12)10 (10)
     Missing381081032714
    Tissue source, n (%)
     Prostatectomy84 (100)249 (100)64 (94)172 (92)29 (88)104 (89)
     TURPc——4 (6)14 (8)4 (12)13 (11)
    PLZF copy number——Not availableNot available
     Gaind3 (4)16 (6)————
     Diploid63 (75)215 (86)————
     Heterozygous deletion11 (13)11 (4)————
     Homozygous deletion7 (8)7 (3)————
    PTEN status
     Intact/diploid43 (51)197 (79)32 (68)97 (82)11 (50)55 (79)
     Loss/any deletion41 (49)52 (21)15 (32)21 (18)11 (50)15 (21)
    • ↵aCategorized as: low, first quartile of mRNA expression; normal, all higher quartiles combined.

    • ↵bSerum prostate specific antigen, in ng/mL.

    • ↵cTransurethral resection of the prostate. Includes one lymph node sample in a patient from PHS.

    • ↵dIncludes one amplification event in the mRNA expression category “normal.”

  • Table 2.

    PLZF expression and ORs for lethal prostate cancer (with 95% CIs) in patients from the HPFS and the PHS

    Quartile of PLZF1st (lowest)2nd3rd4th (highest)
    CasesLethalNonlethalLethalNonlethalLethalNonlethalLethalNonlethal
    4061227927742477
    ModelOR95% CIOR95% CIOR95% CIOR95% CIPtrenda
    AAge-adjusted2.431.30–4.531.000.51–1.961.240.65–2.381.00(ref.)0.011
    BA+clinicalb2.531.20–5.331.300.58–2.891.560.70–3.471.00(ref.)0.026
    CB+ARc3.171.32–7.601.420.62–3.221.680.75–3.791.00(ref.)0.021
    DC in PTEN subsetd3.391.06–10.91.620.55–4.731.390.46–4.231.00(ref.)0.041
    EC+PTENd3.511.03–12.01.640.55–4.841.420.46–4.391.00(ref.)0.046
    • ↵aTrend for linear trend across quartiles.

    • ↵bDemographics and clinical factors: age, calendar year, and Gleason score.

    • ↵cHieronymus and colleagues (2006) AR signature (16).

    • ↵dPTEN status was available only in a subset of 253 patients. Models D and E are both estimated in this subset of patients. Model D includes the same predictors as model C. Model E additionally adjusts for PTEN status. To gauge the change in estimates due to adjusting for PTEN status, compare results from model E with results from model D.

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Cancer Epidemiology Biomarkers & Prevention: 28 (4)
April 2019
Volume 28, Issue 4
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Low Expression of the Androgen-Induced Tumor Suppressor Gene PLZF and Lethal Prostate Cancer
Konrad H. Stopsack, Travis Gerke, Svitlana Tyekucheva, Ying Z. Mazzu, Gwo-Shu Mary Lee, Goutam Chakraborty, Wassim Abida, Lorelei A. Mucci and Philip W. Kantoff
Cancer Epidemiol Biomarkers Prev April 1 2019 (28) (4) 707-714; DOI: 10.1158/1055-9965.EPI-18-1014

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Low Expression of the Androgen-Induced Tumor Suppressor Gene PLZF and Lethal Prostate Cancer
Konrad H. Stopsack, Travis Gerke, Svitlana Tyekucheva, Ying Z. Mazzu, Gwo-Shu Mary Lee, Goutam Chakraborty, Wassim Abida, Lorelei A. Mucci and Philip W. Kantoff
Cancer Epidemiol Biomarkers Prev April 1 2019 (28) (4) 707-714; DOI: 10.1158/1055-9965.EPI-18-1014
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