Identification of a gene frequently mutated in prostate tumors

Although prostate cancer is the second leading cause of cancer death for me n in the United States, the genetics of tumor development are poorly unders tood. Several expressed sequence tagged genes (ESTs) that are expressed pre dominanlty in the prostate have recently been identified, although their ro le in the development and maintenance of the prostate is unknown. Here, we demonstrate that the gene identified as UNIGENE cluster Hs. 104215, which c odes for a message found predominanlty in the prostate, may be important in tumor development. We name this gene PCan1 for Prostate Cancer gene 1. Nor thern blot experiments were performed using RNA isolated from tumor-derived cell lines and human prostate to determine the expression pattern of the g ene. DNA sequencing was used to identify mutations that occurred in tumor t issue. By Northern blot analysis, this gene product was not detectable in L NCaP, DU 145, or PC-3 prostate cancer cell lines, although it was readily o bserved in RNA isolated from total prostate and from dissected central and peripheral regions of prostate. Sequence analysis of genomic DNA from LNCaP , DU 145, or PC-3 cells demonstrated a G/A polymorphism at position 193. An alysis of matched tumor-derived DNA and blood-derived DNA samples from 11 o f 13 patients who had undergone a radical prostatectomy and who were homozy gous for A in blood-derived DNA demonstrated mutation of position 193 in ma tched tumor samples resulting in G/A polymorphism. Sixteen additional patie nt samples were G/A polymorphic in both blood-derived DNA and tumor-derived DNA and two samples were GG in both blood-derived and tumor-derived DNA. O ur results suggest that this gene may be a hot spot for mutation in prostat e cancer, especially because our radiation hybrid mapping located this gene within a region identified in linkage mapping studies of affected families with prostate cancer. Loss of heterozygosity in prostate tumors has also b een reported at the location of PCan1. Further studies to determine the fun ctional role of this candidate tumor suppressor gene are warranted.