ALTERATIONS OF THE RETINOBLASTOMA GENE IN HUMAN PROSTATE ADENOCARCINOMA

The loss or mutational inactivation of the RB1 tumor suppressor gene h as been implicated in the development of a diverse group of human mali gnancies. However, the contribution of the RB1 gene alteration to huma n prostatic carcinogenesis has been poorly understood, Thus far, delet ion of the promoter sequence and exon 21 from one primary tumor specim en and the alterations found in the cell line DU-145, are the only cas es of RB1 mutations reported in human carcinoma of the prostate. This study was designed to determine whether alterations in the structure o r expression of the RB1 gene occur in human prostate carcinoma, and to determine the nature of these changes and the frequency with which th ey occur, One hundred twelve primary prostate tumor tissues and four m etastatic lesions were obtained immediately after surgical resection. The RB1 gene was characterized in 68 tumor DNA samples using Southern analysis and the PG3.8M or H3-8 probes, Band profiles were analyzed by scanning densitometry. Sixty-three tumor DNA samples were analyzed fo r defects in the RBI promoter using polymerase chain reaction (PCR) an d heteroduplex analysis. Alterations in the expression of exons 1-27 w ere analyzed in 79 primary and four metastatic tumor RNAs using RT-PCR . Three of 68 rumors were identified to have gross rearrangement of th e RBI gene or deletion of one allele. One of four stage D tumor specim ens showed truncated RT-PCR products indicating an internal deletion o f RB1 transcripts. In all, 14 of 83 (17%) specimens displayed abnormal ly low levels of RB1 mRNA expression. Furthermore, these alterations o f RBI expression showed a correlation with increasing tumor stage and grade. These results suggest alterations of RB1 mRNA expression occur more frequently in higher stages and grades of prostate cancer and, th us, may be contributing to the malignant progression of a subset of hu man prostate cancer. (C) 1996 Wiley-Liss, Inc.