The TMPRSS2:ERG Rearrangement, ERG Expression, and Prostate Cancer Outcomes: A Cohort Study and Meta-analysis.
ABSTRACT Whether the genomic rearrangement transmembrane protease, serine 2 (TMPRSS2):v-ets erythroblastosis virus E26 oncogene homolog (ERG) has prognostic value in prostate cancer is unclear.
Among men with prostate cancer in the prospective Physicians' Health and Health Professionals Follow-Up Studies, we identified rearrangement status by immunohistochemical assessment of ERG protein expression. We used Cox models to examine associations of ERG overexpression with biochemical recurrence and lethal disease (distant metastases or cancer-specific mortality). In a meta-analysis including 47 additional studies, we used random-effects models to estimate associations between rearrangement status and outcomes.
The cohort consisted of 1,180 men treated with radical prostatectomy between 1983 and 2005. During a median follow-up of 12.6 years, 266 men experienced recurrence and 85 men developed lethal disease. We found no significant association between ERG overexpression and biochemical recurrence [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.78-1.26] or lethal disease (HR, 0.93; 95% CI, 0.61-1.43). The meta-analysis of prostatectomy series included 5,074 men followed for biochemical recurrence (1,623 events), and 2,049 men followed for lethal disease (131 events). TMPRSS2:ERG was associated with stage at diagnosis [risk ratio (RR)(≥T3 vs. T2), 1.23; 95% CI, 1.16-1.30) but not with biochemical recurrence (RR, 1.00; 95% CI, 0.86-1.17) or lethal disease (RR, 0.99; 95% CI, 0.47-2.09).
These results suggest that TMPRSS2:ERG, or ERG overexpression, is associated with tumor stage but does not strongly predict recurrence or mortality among men treated with radical prostatectomy. Impact: This is the largest prospective cohort study to examine associations of ERG overexpression and lethal prostate cancer among men treated with radical prostatectomy. Cancer Epidemiol Biomarkers Prev; 21(9); 1497-509. ©2012 AACR.
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ABSTRACT: Cancer can be defined as a genetic disease, resulting as a consequence of multiple events associated with initiation, promotion and metastatic growth. Cancer results from the loss of control of cellular homeostasis. Cell homeostasis is the result of the balance between proliferation and cell death, while cellular transformation can be viewed as a loss of relationship between these events. Oncogenes and tumour suppressor genes act as modulators of cell proliferation, while the balance of apoptotic and anti-apoptotic genes controls cell death. All cancer cells acquire similar sets of functional capacities: (1) independence from mitogenic/growth signals; (2) loss of sensitivity to "anti-growth" signals; (3) evade apoptosis; (4) Neo-angiogenic conversion; (5) release from senescence; and (6) invasiveness and metastasis. One of the goals of molecular biology is to elucidate the mechanisms that contribute to the development and progression of cancer. Such understanding of the molecular basis of cancer will provide new possibilities for: (1) earlier detection as well as better diagnosis and staging of disease with detection of minimal residual disease recurrences and evaluation of response to therapy; (2) prevention; and (3) novel treatment strategies. We feel that increased understanding of ETS-regulated biological pathways will directly impact these areas. ETS proteins are transcription factors that activate or repress the expression of genes that are involved in various biological processes, including cellular proliferation, differentiation, development, transformation and apoptosis. Identification of target genes that are regulated by a specific transcription factor is one of the most critical areas in understanding the molecular mechanisms that control transcription. Furthermore, identification of target gene promoters for normal and oncogenic transcription factors provides insight into the regulation of genes that are involved in control of normal cell growth, and differentiation, as well as provide information critical to understanding cancer development. This review will highlight the current understanding of ETS genes and their role in cancer.European Journal of Cancer 12/2005; 41(16):2462-78. · 5.06 Impact Factor
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ABSTRACT: • To describe metastasis-free survival (MFS) and overall survival (OS) among men with prostate-specific antigen (PSA)-recurrent prostate cancer after radical prostatectomy who did not receive additional therapy until metastasis, using a multicentre database capturing a wide ethnic mix. • A retrospective analysis of the Center for Prostate Disease Research National Database (comprised of five US military hospitals and one civilian centre) was performed for patients with PSA relapse (≥ 0.2 ng/mL) after radical prostatectomy who had no additional therapy until the time of radiographic metastatic disease. • We investigated factors influencing metastasis and all-cause mortality using univariate and multivariate Cox regression analysis. • There were a total of 346 men who underwent radical prostatectomy between May 1983 and November 2008 and fulfilled the entry criteria. All patients had information on survival and 190 men had information on metastasis. Among patients with survival data (n= 346), 10-year OS was 79% after a median follow-up of 8.6 years from biochemical recurrence. • Among men with metastasis data (n= 190), 10-year MFS was 46% after a median follow-up of 7.5 years. • In Cox regressions, four clinical factors (Gleason score, pathological stage, time to PSA relapse and PSA doubling time), as well as age, were predictive of OS and/or MFS in univariate analysis, although only PSA doubling time (≥ 9 vs 3-8.9 vs <3 months) remained independently predictive of these outcomes in multivariate analysis (P < 0.001). • This multicentre multi-ethnic dataset shows that OS and MFS can be extensive for men with PSA-recurrent prostate cancer, even in the absence of further therapy before metastasis. • This unique patient cohort, the second largest of its type after the Johns Hopkins cohort, confirms that PSA doubling time is the strongest determinant of OS and MFS in men with PSA-recurrent disease. • Longer follow-up and more events will be required to determine whether other variables may also contribute to these outcomes.BJU International 11/2010; 108(3):378-85. · 3.05 Impact Factor
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ABSTRACT: Atypical cribriform lesions (ACLs) of the prostate consist of cribriform glands lined with cytologically malignant cells with partial or complete basal cell lining. It may represent cribriform "high-grade prostatic intraepithelial neoplasia" (HGPIN) or "intraductal carcinoma of the prostate" (IDC-P), which is almost always associated with clinically aggressive prostate carcinoma (PCa). Distinction between these 2 lesions has profound clinical significance, especially on needle biopsies. However, there are lesions that do not fully satisfy the criteria for IDC-P yet are worse than typical HGPIN and are difficult to distinguish based on morphologic criteria alone. To better understand the biologic and molecular basis of distinction between cribriform HGPIN and IDC, we used break-apart fluorescence in-situ hybridization assay to assess ETS gene aberrations, a specific and commonest molecular alteration involving PCa, in a cohort of 16 isolated ACL, presumed to be an isolated cribriform HGPIN, and 45 carcinoma-associated ACL (ACL-PCa) on radical prostatectomy specimens, presumed to be spectrum of IDC-P. The latter was further divided into 2 groups: group A with marked nuclear atypia (nuclear size 6xnormal or larger) and/or comedonecrosis (n=21) and group B that did not fulfill these criteria (n=24). Overall, ERG rearrangement was absent (0 of 16) in isolated cribriform HGPIN, whereas present in 75% (36 of 48) of IDC-P, of which 65% (23 of 36) were through deletion and 35% (13 of 36) through insertion. Notably, 17% (6 of 36) of the IDC-P showed duplication of ERG rearrangement in combination with deletion of 5'-ERG. Hundred percent (34 of 34) of the IDC-P showed concordance of ERG rearrangement status with adjacent invasive carcinoma. There was no difference between the 2 groups of IDC-P lesions regarding prevalence of ERG rearrangement (group A 79% vs. group B 74%) and EDel2+ (20% vs. 15%). No case with ETV1, ETV4, or ETV5 rearrangement was identified. Our molecular data suggest that isolated cribriform HGPIN and IDC-P are biologically distinct lesions. Majority of ACL-PCa most likely represent intraductal spread of PCa. There is a significant overlap between IDC-P and HGPIN at the lower grade morphologic spectrum. ERG break-apart fluorescence in-situ hybridization assay provides insight into understanding the molecular basis of cribriform HGPIN and IDC-P and has potential clinical implications in their distinction on needle biopsies.The American journal of surgical pathology 03/2010; 34(4):478-85. · 4.06 Impact Factor