Browsing by Author "Linehan, WM"

Now showing 1 - 5 of 5
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    Differential expression of the mismatch repair gene hMSH2 in malignant prostate tissue is associated with cancer recurrence
    (2002) Velasco, A; Hewitt, SM; Albert, PS; Saboorian, MH; Rosenberg, H; Martinez, C; Sagalowsky, AI; McConnell, JD; Linehan, WM; Leach, FS
    BACKGROUND. Mismatch repair (MMR) genes are responsible for coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating mutations in MMR genes have been described in sporadic cancers and a hereditary cancer predisposition syndrome. Mismatch repair deficiency causes instability at microsatellites and increased mutation rates. Although microsatellite instability (MSI) has been described in high-grade and lymph node positive prostate carcinoma specimens, an analysis comparing hMSH2 expression, MSI, and outcome in clinically organ confined prostate carcinoma has not been reported.
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    Molecular alterations in primary prostate cancer after androgen ablation therapy
    (AMER ASSOC CANCER RESEARCH, 2005) Best, CJM; Gillespie, JW; Yi, YJ; Chandramouli, GVR; Perlmutter, MA; Gathright, Y; Erickson, HS; Georgevich, L; Tangrea, MA; Duray, PH; Gonzalez, S; Velasco, A; Linehan, WM; Matusik, RJ; Price, DK; Figg, WD; Emmert Buck, MR; Chuaqui, RF
    Purpose: After an initial response to androgen ablation, most prostate tumors recur, ultimately progressing to highly aggressive androgen-independent cancer. The molecular mechanisms underlying progression are not well known in part due to the rarity of androgen-independent Samples from primary and-metastatic sites.
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    Molecular differentiation of high- and moderate-grade human prostate cancer by cDNA microarray analysis
    (LIPPINCOTT WILLIAMS & WILKINS, 2003) Best, CJM; Leiva, IM; Chuaqui, RF; Gillespie, JW; Duray, PH; Murgai, M; Zhao, YD; Simon, R; Kang, JJ; Green, JE; Bostwick, DG; Linehan, WM; Emmert Buck, MR
    The prognosis of men with moderate-grade prostate cancer is uncertain. At present, there are few if any reliable molecular markers that can distinguish moderate-grade tumors from those that behave more aggressively. To better understand the molecular basis of human prostate cancer and potentially provide information toward more accurate prognosis, we measured and analyzed gene expression profiles of 13 high- and moderate-grade human prostate tumors using cDNA microarrays. The expression of 136 genes was observed to differ significantly (P < 0.001) between normal prostate and tumors using one-sample t testing and Wilcoxon ranking. Hierarchical clustering of genes demonstrated a relatively similar pattern of differential expression across the tumors. However, importantly, permutation t tests (two-tailed P < 0.001) revealed 21 genes whose expression profiles segregated moderate- and high-grade tumors from each other, which was significantly (P < 0.03) Greater than what was expected by chance. These results were compared in silico with prostate cancer profiling efforts performed by other groups, including a meta-analysis of four data sets. which validated many of the dysregulated genes. We suggest that these data provide insight into the molecular nature of clinically aggressive prostate cancer.
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    Serum proteomic patterns for detection of prostate cancer
    (OXFORD UNIV PRESS INC, 2002) Petricoin, EF; Ornstein, DK; Paweletz, CP; Ardekani, A; Hackett, PS; Hitt, BA; Velassco, A; Trucco, C; Wiegand, L; Wood, K; Simone, CB; Levine, PJ; Linehan, WM; Emmert Buck, MR; Steinberg, SM; Kohn, EC; Liotta, LA
    Pathologic states within the prostate may be reflected by changes in serum proteomic patterns. To test this hypothesis, we analyzed serum proteomic mass spectra with a bioinformatics tool to reveal the most fit pattern that discriminated the training set of sera of men with a histopathologic diagnosis of prostate cancer (serum prostate-specific antigen [PSA] greater than or equal to 4 ng/mL) from those men without prostate cancer (serum PSA level < 1 ng/mL). Mass spectra of blinded sera (N = 266) from a test set derived from men with prostate cancer or men without prostate cancer were matched against the discriminating pattern revealed by the training set. A predicted diagnosis of benign disease or cancer was rendered based on similarity to the discriminating pattern discovered from the training set. The proteomic pattern correctly predicted 36 (95%, 95% confidence interval [CI] = 82% to 99%) of 38 patients with prostate cancer, while 177 (78%, 95% CI = 72% to 83%) of 228 patients were correctly classified as having benign conditions. For men with marginally elevated PSA levels (4-10 ng/mL; n = 137), the specificity was 71%. If validated in future series, serum proteomic pattern diagnostics may be of value in deciding whether to perform a biopsy on a man with an elevated PSA level.
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    Signal pathway profiling of prostate cancer using reverse phase protein arrays
    (2003) Grubb, RL; Calvert, VS; Wulkuhle, JD; Paweletz, CP; Linehan, WM; Phillips, JL; Chuaqui, R; Valasco, A; Gillespie, J; Emmert-Buck, M; Liotta, LA; Petricoin, EF
    Reverse phase protein arrays represent a new proteomics microarray technology with which to study the fluctuating state of the proteome in minute quantities of cells. The activation status of cell signaling pathways controls cellular fate and deregulation of these pathways underpins carcinogenesis. Changes in pathway activation that occur between early stage prostatic epithelial lesions, prostatic stroma and the extracellular matrix can be analyzed by obtaining pure populations of cell types by laser capture microdissection (LCM) and analyzing the relative states of several key phosphorylation points within the cellular circuitry. We have applied reverse phase protein array technology to analyze the status of key points in cell signaling involved in pro-survival, mitogenic, apoptotic and growth regulation pathways in the progression from normal prostate epithelium to invasive prostate cancer. Using multiplexed reverse phase protein arrays coupled with LCM, the states of signaling changes during disease progression from prostate cancer study sets were analyzed. Focused analysis of phosphospecific endpoints revealed changes in cellular signaling events through disease progression and, between patients. We have used a new protein array technology to study specific molecular pathways believed to be important in cell survival and progression from normal epithelium to invasive carcinoma directly from human tissue specimens. With the advent of molecular targeted therapeutics, the identification, characterization and monitoring of the signaling events within actual human biopsies will be critical for patient-tailored therapy.