RESUMO
PURPOSE: We analyzed the expression of genes to identify reliable molecular markers in the diagnosis and progression of prostate cancer. EXPERIMENTAL DESIGN: Gene expression profiling was done using HG-U133 set microarrays in 32 prostate cancer and 8 benign tissues of patients with cancer. Expression levels of 11 genes were selected for quantitative real-time PCR evaluation in 52 prostate cancer and 20 benign tissues. Further, to assess transcriptional inactivation, we analyzed the promoter methylation of genes by quantitative methylation-specific PCR in 62 tumor and 36 benign tissues. RESULTS: Our results showed a significant down-regulation in the mRNA expression levels of PRIMA1, TU3A, PDLIM4, FLJ14084, SVIL, SORBS1, C21orf63, and KIAA1210 and up-regulation of FABP5, SOX4, and MLP in prostate cancer tissues by TaqMan real-time PCR. Quantitative methylation-specific PCR of PDLIM4, SVIL, PRIMA1, GSTP1, and PTGS2 detected prostate carcinoma with a sensitivity of 94.7%, 75.4%, 47.4%, 89.5%, and 87.7%, and a specificity of 90.5%, 75%, 54.2%, 95.8%, and 90.2%, respectively. Using this panel of methylation markers in combination, we were able to distinguish between prostate cancer and adjacent benign tissues with sensitivities and specificities of about 90% to 100%. Our data provide evidence of transcriptional repression of the putative tumor suppressor gene PDLIM4 by hypermethylation. CONCLUSIONS: Our analysis revealed differential expression of eight down-regulated and three up-regulated genes, implicating their role in prostate cancer development and progression. We further showed that the hypermethylation of PDLIM4 gene could be used as a sensitive molecular tool in detection of prostate tumorigenesis.
Assuntos
Metilação de DNA , Proteínas de Ligação a DNA/genética , Neoplasias da Próstata/patologia , Idoso , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Ciclo-Oxigenase 2/genética , Metilases de Modificação do DNA/antagonistas & inibidores , Decitabina , Inibidores Enzimáticos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa S-Transferase pi/genética , Humanos , Proteínas com Domínio LIM , Masculino , Proteínas de Membrana/genética , Proteínas dos Microfilamentos/genética , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Reação em Cadeia da Polimerase/métodos , Neoplasias da Próstata/genéticaRESUMO
Genetic defects in CHEK2 and TP53 have been implicated in prostate cancer development. However, the interaction of these two genes in prostate cancer tumorigenesis has not been investigated. We previously described 11 CHEK2 mutations in a group of 84 primary prostate tumors. In this report, we screened the same group of tumors for TP53 mutations and revealed nine somatic and two germline mutations. One germline TP53 mutation (c.408A > T/p.Gln136His) and two somatic mutations (c.1022T > G/p.Phe341Cys and c.108-109ins22/p.His37fsX13) are novel to human cancer. More interestingly, CHEK2 and TP53 mutations were observed to be mutually substituted in these tumors. Analysis of five commonly used prostate cancer cell lines revealed that four cell lines harboring TP53 mutations carry no CHEK2 mutation while the only cell line (LNCaP) carrying wild-type TP53 harbors a CHEK2 mutation. The novel CHEK2 mutation (c.1160C>T/p.Thr387Asn) identified in LNCaP cells changes amino acid Thr387 to Asn which has been shown to impair CHEK2 autophosphorylation and activation. Our data suggest that the CHEK2 and TP53 mutations can substitute each other in at least 25% (21/84) of prostate cancers and that DNA damage-signaling pathway plays an important role in prostate cancer tumorigenesis.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Mutação/genética , Neoplasias da Próstata/genética , Proteína Supressora de Tumor p53/genética , Idoso , Sequência de Bases , Linhagem Celular Tumoral , Análise Mutacional de DNA/métodos , Duplicação Gênica , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Neoplasias da Próstata/patologiaRESUMO
OBJECTIVES: To provide an overview of emerging applications for and challenges associated with biospecimen collection for evaluating personalized disease risk and/or treatment response in cancer clinical trials. DATA SOURCES: Published nursing and medical literature. CONCLUSION: Blood- and tissue-based biomarkers are increasingly utilized to identify the molecular signatures of disease that can inform the determination of a course of treatment in a very precise manner. There are challenges for the oncology nurse related to specimen collection, processing, analysis, and translation to precision treatment. IMPLICATIONS FOR NURSING PRACTICE: It is important for nurses to have appropriate training and a working understanding of the procedures for biospecimen collection and how biospecimen analyses can inform precision assessment of risk and prognosis.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias/diagnóstico , Enfermagem Oncológica/métodos , Manejo de Espécimes/métodos , Bioensaio , Ensaios Clínicos como Assunto , Humanos , Neoplasias/enfermagem , Assistência Centrada no Paciente/métodos , Medicina de Precisão/enfermagem , Manejo de Espécimes/enfermagemRESUMO
PURPOSE: Phyllodes tumor of the prostate is a rare neoplasm of uncertain malignant potential. We studied a large series of phyllodes tumors to define the combination of histological features that are most useful for predicting patient outcome. MATERIALS AND METHODS: A total of 23 cases were obtained from our collective files from 1973 to 2002, and numerous clinical and pathological features were evaluated. A review of the reported cases of phyllodes tumor of the prostate was done. RESULTS: Patient age was 25 to 86 years (mean 55) and they usually presented with urinary obstructive symptoms and hematuria. The diagnosis was made in 18 tumors by transurethral resection, in 2 by enucleation, in 1 by tumor resection and in 2 by prostatectomy. We analyzed 5 histological features, including cellularity (scale of 1 to 3), cytologic atypia (scale of 1 to 3), the number of mitotic figures per 10 high power fields, the stroma-to-epithelium ratio (low or high) and necrosis (present or absent). This combination of features revealed that 14 cases were low grade phyllodes tumor, 7 were intermediate grade and 2 were high grade with the high grade cases characterized by increased cellularity, severe cytological atypia, more than 5 mitotic figures per 10 high power fields and a high stroma-to-epithelium ratio, indicating stromal overgrowth. Immunohistochemical studies of 8 tumors revealed consistent, intense cytoplasmic immunoreactivity in stromal cells for vimentin and actin, in luminal epithelial cells for prostate specific antigen, prostatic acid phosphatase and broad-spectrum keratin AE1/AE3, and in basal cells for high molecular weight keratin 34beta-E12. Recurrence was seen in 7 of 14 low grade tumors (50%) and in 1 patient low grade sarcoma emerged with subsequent distant metastases 14 years after initial diagnosis following 5 recurrences. Recurrence was seen in 6 of 7 intermediate grade tumors and low grade sarcoma emerged with subsequent abdominal wall metastases in 1 patient 11 years after initial diagnosis following 3 recurrences. The phyllodes tumor recurred in each patient with high grade tumors with a time to first recurrence of 6 and 0.2 years, respectively. Distant metastases developed in these 2 patients. CONCLUSIONS: Histological grading of prostatic phyllodes tumors is predictive of short-term outcome based on the combination of stromal cellularity, cytological atypia, number of mitotic figures and the stroma-to-epithelium ratio. However, these tumors usually recur after transurethral prostatic resection and they are often locally aggressive with time. The emergence of overt sarcoma and metastatic disease is more frequent than previously recognized. Complete resection at initial diagnosis appears to be indicated.