Identification of Genetic Markers for Prostatic Cancer Progression

Abstract

SUMMARY:Despite the high incidence of prostate cancer, only limited data are available on genes or chromosomes specifically involved in its initiation and progression. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded, tissues at different times in prostatic tumor progression to screen the tumor genome for gains and losses. Our panel included specimens derived from 56 different patients: 23 patients with primary, prostate-confined carcinomas; 18 patients with regional lymph node metastases; and 15 patients with distant metastases. Chromosome arms that most frequently showed losses, included 13q (55%), 8p (48%), 6q (43%), 5q (32%), 16q (25%), 18q (20%), 2q (18%), 4q (18%), 10q (18%), and Y (16%). Gains were often seen of chromosome arms 8q (36%), 17q (23%), Xq (23%), 7q (21%), 3q (18%), 9q (18%), 1q (16%), Xp (16%). Furthermore, specific high-level amplifications, eg, of 1q21, 1q25, and Xq12 to q13, were found in metastatic cancers. A significant accumulation of genetic changes in distant metastases was observed, eg, loss of 10q (p ϭ 0.03) and gain of 7q (p ϭ 0.03) sequences. In addition, investigation of a potential biomarker identified in previous studies by our group, ie, extra copies of #7 and/or #8, revealed a high prevalence of 7pq and/or 8q gain in the distant metastases (p ϭ 0.02). Importantly, gains were observed more frequently in tumors derived from progressors after radical prostatectomy, than in nonprogressors (mean time of follow-up, 74 months). Specifically, gain of chromosome 7pq and/or 8q sequences appeared an accurate discriminator between the progressors and nonprogressors. Multivariate analysis showed a significant correlation between progressive disease and the number of chromosomes with gains. This correlation also held true when stage (p ϭ 0.007) or grade (p ϭ 0.002) were taken into account. Likewise, this applied for gain of chromosome 7pq and/or 8q sequences (p ϭ 0.03 and p ϭ 0.005 for stage or grade, respectively). Additionally, an increase in the number of chromosomes with gains per case was related to a decrease in biochemical progression-free survival (P trend Ͻ0.001). More specifically, the gain of 7pq and/or 8q sequences markedly reduced the biochemical progression-free survival (p Ͻ 0.001). In conclusion, this study has, firstly, documented the spectrum of chromosomal alterations in subsequent stages of prostate cancer, a number of which had not been described previously. It allowed us to identify chromosomal regions related to advanced tumor stage, ie, loss of 10q24 and gain of 7q11.2 and/or 7q31 sequences. Secondly, gain of 7pq and/or 8q was identified as a potential genetic discriminator between progressors and nonprogressors after radical surgery. (Lab Invest 2000, 80:931-942). P rostate cancer is the most commonly diagnosed, male noncutaneous malignancy and the second leading cause of cancer-related death in men in Western industrialized countries. Its incidence is continuously rising, with over 200,000 new cases diagnosed each year, r...

Regional over-representations on chromosomes 1q, 3q and 7q in the progression of hepatitis B virus-related hepatocellular carcinoma

“…Apart from its participation in hepatocellular carcinoma, gains of 1q21-q22 were also shown related to the progression of other human cancers. The presence of 1q21-q22 amplicon in metastatic lesions of lung cancer, 24,25 head and neck squamous cell carcinoma 26 and prostate cancer 27,28 has further put forward a role for this region in tumor dissemination. In an attempt to elucidate for the underlying affected genes, positional mapping from our group has previously refined the 1q21-q22 amplicon in hepatocellular carcinoma to three affected loci, in which the overexpression of JTB, SHC1, CCT3 and COPA was indicated.…”

“…Gains on 7q have also been signified in the advanced tumor stages of prostate cancer and appeared to be potential genetic discriminators for the prognosis of patients after radical prostatectomy. 27 It has been further suggested that the distal 7q3 regions are likely to harbor genes affecting the progression of prostate cancer from latent to invasive disease. 34 In chronic infections of the liver, elevated levels of hepatocyte growth factor (7q21) are often detected and have been shown to induce upregulation of MET expression in hepatocellular carcinoma.…”

Prostate cancer incidence varies among males from different Y-chromosome lineages

“…Based on genomewide scans, such susceptibility loci and genetic alterations were attributed to chromosomes, 1,7,8,10,12,17,18,20, X, and the Y chromosome. [9][10][11][12][13][14] A large amount of data has been generated about alterations, aberrations, rearrangements, gain, or loss of Y-chromosome materials in prostate cancer using different techniques of molecular cytogenetics. [15][16][17][18][19][20] The simple fact that the Y chromosome and prostate cancer have male-specificity in common lead many researchers to investigate if there is Y involvement in such a male-specific cancer, however, yet there is no clear conclusions.…”

Amplification and Overexpression of Elongin C Gene Discovered in Prostate Cancer by cDNA Microarrays

“…The gain of 8q is one of the most common chromosomal alterations in late-stage prostate cancer. By CGH, it is found in about 70% to 90% of hormone-refractory or metastatic prostate carcinomas, and it seems to be associated with poor prognosis (Alers et al, 2000;Cher et al, 1996;Nupponen et al, 1998b). We and others have previously mapped the minimal commonly amplified regions to two separate chromosomal fragments, 8q21 and 8q23-q24 (Cher et al, 1996;Nupponen et al, 1998b).…”