RESUMO
BACKGROUND: TMPRSS2:ERG fusions are promising prostate cancer biomarkers. Because they can occur in multiple forms in a single cancer specimen, we developed a quantitative PCR test that detects both type III and type VI TMPRSS2:ERG fusions. The assay is quantified from a standard curve determined with a plasmid-cloned type III TMPRSS2:ERG fusion target. METHODS: We collected expressed prostatic secretion (EPS) under an institutional review board-approved, blinded, prospective study from 74 patients undergoing transrectal ultrasound-guided biopsy for prostate cancer. We compared the characteristic performance of the test for type III and type VI TMPRSS2:ERG fusions in predicting biopsy outcome and distinguishing between high and low Gleason scores with similar tests for the expression of PCA3 and DNA methylation levels of the APC, RARB, RASSF1, and GSTP1 genes. We used logistic regression to analyze the effects of multiple biomarkers in linear combinations. RESULTS: Each test provided a significant improvement in characteristic performance over baseline digital rectal examination (DRE) plus serum prostate-specific antigen (PSA); however, the test for type III and type VI TMPRSS2:ERG fusions yielded the best performance in predicting biopsy outcome [area under the curve (AUC) 0.823, 95% CI 0.728-0.919, P < 0.001] and Gleason grade >7 (AUC 0.844, 95% CI 0.740-0.948, P < 0.001). CONCLUSIONS: Although each test appears to have diagnostic value, PSA plus DRE plus type III and type VI TMPRSS2:ERG provided the best diagnostic performance in EPS specimens.
Assuntos
Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/diagnóstico , Proteína da Polipose Adenomatosa do Colo/genética , Idoso , Antígenos de Neoplasias/análise , Biomarcadores Tumorais/análise , Biópsia , Metilação de DNA , Variação Genética , Glutationa S-Transferase pi/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Receptores do Ácido Retinoico/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Supressoras de Tumor/genética , UltrassonografiaRESUMO
BACKGROUND: Advances in biotechnology have raised expectations that biomarkers, including genetic profiles, will yield information to accurately predict outcomes for individuals. However, results to date have been disappointing. In addition, statistical methods to quantify the predictive information in markers have not been standardized. METHODS: We discuss statistical techniques to summarize predictive information, including risk distribution curves and measures derived from them, that relate to decision making. Attributes of these measures are contrasted with alternatives such as receiver operating characteristic curves, R(2), percent reclassification, and net reclassification index. Data are generated from simple models of risk conferred by genetic profiles for individuals in a population. Statistical techniques are illustrated, and the risk prediction capacities of different risk models are quantified. RESULTS: Risk distribution curves are most informative and relevant to clinical practice. They show proportions of subjects classified into clinically relevant risk categories. In a population in which 10% have the outcome event and subjects are categorized as high risk if their risk exceeds 20%, we identified some settings where more than half of those destined to have an event were classified as high risk by the risk model. Either 150 genes each with odds ratio of 1.5 or 250 genes each with odds ratio of 1.25 were required when the minor allele frequencies are 10%. We show that conclusions based on receiver operating characteristic curves may not be the same as conclusions based on risk distribution curves. CONCLUSIONS: Many highly predictive genes will be required to identify substantial numbers of subjects at high risk.