Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome

被引:216
作者
Yoshimoto, Maisa
Joshua, Anthony M.
Cunha, Isabela W. [2 ]
Coudry, Renata A. [2 ]
Fonseca, Francisco P. [3 ]
Ludkovski, Olga
Zielenska, Maria [4 ]
Soares, Fernando A. [2 ]
Squire, Jeremy A. [1 ,5 ]
机构
[1] Princess Margaret Hosp, Ontario Canc Inst, Div Appl Mol Oncol, Toronto, ON M5G 2M9, Canada
[2] Hosp Canc, Dept Pathol, Sao Paulo, Brazil
[3] Hosp Canc, Dept Pelv Surg, Sao Paulo, Brazil
[4] Hosp Sick Children, Dept Pathol & Lab Med, Toronto, ON M5G 1X8, Canada
[5] Univ Toronto, Fac Med, Dept Med Biophys, Toronto, ON, Canada
关键词
interphase FISH; PTEN haploinsufficiency; prognosis; biomarker; biochemical recurrence;
D O I
10.1038/modpathol.2008.96
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
TMPRSS2:ERG gene fusions and PTEN deletions are the most common genomic aberrations in prostate cancer. Recent work has suggested that the TMPRSS2: ERG fusion is associated with a more aggressive phenotype. Similarly, PTEN deletion has been associated with biochemical recurrence and lymph node metastasis. To date, there has been no systematic analysis of the combined influence of genomic PTEN deletion with TMPRSS2: ERG gene fusions on clinical parameters of prostate cancer progression. We carried out a retrospective analysis of 125 prostate cancers with known clinical outcome using interphase fluorescence in situ hybridization to detect the relative prevalence of TMPRSS2: ERG rearrangements and/or PTEN genomic deletions. TMPRSS2: ERG rearrangement was found in 60 of 125 (48%) prostate cancers. Duplication of TMPRSS2: ERG fusion was observed in seven (6%) tumors. Gleason grade (P = 0.0002)/score (P = 0.001), median tumor volume (P = 0.0024), preoperative PSA (P = 0.001) and perineural invasion (P = 0.0304) were significantly associated with biochemical recurrence by univariate analysis with TMPRSS2: ERG approaching significance (P = 0.0523). By multivariate analysis, relevant factors associated with recurrence were Gleason scores 7 (P = 0.001) and 8-10 (P = 0.015), PTEN homozygous deletion (P = 0.013) and concurrent TMPRSS2: ERG fusion and PTEN deletion (P = 0.036). Kaplan-Meier analysis indicated that the presence of TMPRSS2: ERG fusion was marginally less favorable in comparison to no fusion. Duplication of fusion gene showed worse prognosis. It was possible to determine the relative frequencies of PTEN deletion and/or TMPRSS2: ERG fusions in 82 of 125 prostate cancers. With biochemical recurrence as an endpoint, the genomic biomarkers identified three patient groups: (1) 'poor genomic grade' characterized by both PTEN deletion and TMPRSS2: ERG fusions (23/82, 28%); (2) 'intermediate genomic grade' with either PTEN deletion or TMPRSS2: ERG fusion (35/82, 43%) and (3) 'favorable genomic grade' in which neither rearrangement was present (24/82, 29%). Kaplan-Meier and multivariate analysis indicate that TMPRSS2: ERG fusion and PTEN loss together are a predictor of earlier biochemical recurrence of disease.
引用
收藏
页码:1451 / 1460
页数:10
相关论文
共 48 条
  • [1] ETS-TMPRSS2 fusion gene products in prostate cancer
    Ahlers, Christoph M.
    Figg, William D.
    [J]. CANCER BIOLOGY & THERAPY, 2006, 5 (03) : 254 - 255
  • [2] Phosphorylation of HDM2 by Akt
    Ashcroft, M
    Ludwig, RL
    Woods, DB
    Copeland, TD
    Weber, HO
    MacRae, EJ
    Vousden, KH
    [J]. ONCOGENE, 2002, 21 (13) : 1955 - 1962
  • [3] Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer
    Attard, G.
    Clark, J.
    Ambroisine, L.
    Fisher, G.
    Kovacs, G.
    Flohr, P.
    Berney, D.
    Foster, C. S.
    Fletcher, A.
    Gerald, W. L.
    Moller, H.
    Reuter, V.
    De Bono, J. S.
    Scardino, P.
    Cuzick, J.
    Cooper, C. S.
    [J]. ONCOGENE, 2008, 27 (03) : 253 - 263
  • [4] Loss of PTEN is associated with progression to androgen independence
    Bertram, Jerod
    Peacock, James W.
    Fazli, Ladan
    Mui, Alice L. -F.
    Chung, Stephen W.
    Cox, Michael E.
    Monia, Brett
    Gleave, Martin E.
    Ong, Christopher J.
    [J]. PROSTATE, 2006, 66 (09) : 895 - 902
  • [5] PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis
    Besson, A
    Robbins, SM
    Yong, VW
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1999, 263 (03): : 605 - 611
  • [6] Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor
    Brunet, A
    Bonni, A
    Zigmond, MJ
    Lin, MZ
    Juo, P
    Hu, LS
    Anderson, MJ
    Arden, KC
    Blenis, J
    Greenberg, ME
    [J]. CELL, 1999, 96 (06) : 857 - 868
  • [7] Regulation of cell death protease caspase-9 by phosphorylation
    Cardone, MH
    Roy, N
    Stennicke, HR
    Salvesen, GS
    Franke, TF
    Stanbridge, E
    Frisch, S
    Reed, JC
    [J]. SCIENCE, 1998, 282 (5392) : 1318 - 1321
  • [8] TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions
    Cerveira, Nuno
    Ribeiro, Franclim R.
    Peixoto, Ana
    Costa, Vera
    Henrique, Rui
    Jeronimo, Carmen
    Teixeira, Manuel R.
    [J]. NEOPLASIA, 2006, 8 (10): : 826 - 832
  • [9] Role of the TMPRSS2-ERG gene fusion in prostate cancer
    Chinnaiyan, Arul M.
    [J]. NEOPLASIA, 2008, 10 (02): : 177 - U23
  • [10] Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
    Datta, SR
    Dudek, H
    Tao, X
    Masters, S
    Fu, HA
    Gotoh, Y
    Greenberg, ME
    [J]. CELL, 1997, 91 (02) : 231 - 241