RESUMO
BACKGROUND: Carcinoma of the prostate (CaP) is a serious health problem. The altered molecular mechanisms that lead to this disease are poorly understood. METHODS: Specimens from radical prostatectomies and blood were collected from 18 CaP surgery patients. For CGH studies, 20 CaP-related samples (16 Gleason grade 3, 3 higher grades, 1 BPH sample) and 18 samples of patient-matched normal epithelial cells were obtained by laser-assisted microdissection from frozen sections of the 18 prostatectomy specimens. High resolution SMRT aCGH was used to compare genomic profiles of prostatic samples to patient-matched blood and pooled female DNA. TMPRSS2-ERG fusion transcript analysis was performed by RT-PCR in relation to alterations detected at the TMPRSS2 locus. RESULTS: Our comprehensive aCGH approach allowed us to define 35 regions of recurrent alterations while excluding germline copy number polymorphisms. Novel regions identified include 2q14.2, containing INHBB, and 17q21.31. The TMPRSS2 locus at 21q22.3 may be a hotspot for rearrangements with 75% of the alterations resulting in the expression of a TMPRSS2-ERG fusion transcript. Differences in fusion expression in different areas in an individual tumor focus and expression in adjacent normal epithelium supported intrafocal heterogeneity and field cancerization, respectively. Both features challenge our efforts to develop more objective markers for diagnosis and prediction of the severity of CaP. CONCLUSION: The high-density array enabled precise mapping of genomic alterations and consequently definition of minimum altered regions smaller than previously reported thus facilitating identification of those genes that contribute to the cancer transformation process.
Assuntos
Adenocarcinoma/genética , Hibridização Genômica Comparativa , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Adenocarcinoma/patologia , Quebra Cromossômica , Cromossomos Artificiais Bacterianos , Cromossomos Humanos , Progressão da Doença , Células Epiteliais/fisiologia , Dosagem de Genes , Genômica/métodos , Humanos , Masculino , Microdissecção , Polimorfismo Genético , Próstata/patologia , Próstata/fisiologia , Neoplasias da Próstata/patologiaRESUMO
Identification of proteomic alterations associated with early stages in the development of prostate cancer may facilitate understanding of progression of this highly variable disease. Matched normal, high-grade prostatic intraepithelial neoplasia (hPIN) and prostate cancer cells of predominantly Gleason grade 3 were procured by laser capture microdissection from serial sections obtained from snap-frozen samples dissected from 22 radical prostatectomy specimens. From these cells, protein profiles were generated by surface-enhanced laser desorption/ionization-time of flight mass spectrometry. A 24-kDa peak was observed at low or high intensity in profiles of prostate cancer cells in 19 of 27 lesions and at low intensity in 3 of 8 hPIN lesions but was not detectable in matched normal cells. SDS-PAGE analysis of prostate cancer and matched normal epithelium confirmed expression of a prostate cancer-specific 24-kDa protein. Mass spectrometry and protein data-based analysis identified the protein as the dimeric form of mature growth differentiation factor 15 (GDF15). The increased expression of mature GDF15 protein in prostate cancer cells cannot be explained on the basis of up-regulation of GDF15 mRNA because reverse transcription-PCR analysis showed similar amounts of transcript in normal, hPIN, and prostate cancer cells that were obtained by laser capture microdissection in the same set of serial sections from which the protein profiles were obtained. Our findings suggest that early prostate carcinogenesis is associated with expression of mature GDF15 protein.
Assuntos
Adenocarcinoma/metabolismo , Proteínas de Membrana/biossíntese , Neoplasias da Próstata/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patologia , Sequência de Aminoácidos , Proteínas Morfogenéticas Ósseas , Fator 15 de Diferenciação de Crescimento , Humanos , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Dados de Sequência Molecular , Neoplasia Prostática Intraepitelial/genética , Neoplasia Prostática Intraepitelial/metabolismo , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Análise Serial de Proteínas/métodos , Precursores de Proteínas/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Traumatic self-amputation of the penis by a psychotic patient is rare. Microvascular replantation is the favored management approach. There are no known cases of self-amputation followed by ingestion of the stump and subsequent replantation. A 51-year-old patient with paranoid schizophrenia presented 2 hours following penile amputation. He had swallowed the excised portion, which was endoscopically retrieved from the stomach in the emergency department. Successful reattachment was achieved including microvascular repair of the dorsal penile arteries without cavernosal arterial anastamoses. A Winter's shunt was performed to improve venous circulation. The patient has been followed for 3 years from the date of repair. He has adequate erection for intercourse and good urinary function, but has experienced sensory loss over the dorsal aspect and glans and urethral stricture dilation. This is the first report of replantation following ingestion of an amputated penis.