High frequency of deletion on chromosome 9p21 may harbor several tumor-suppressor genes in human prostate cancer

Perinchery, Geetha; Bukurov, Nikola; Nakajima, Koichi; Chang, James J.; Li, Long‐Cheng; Dahiya, Rajvir

doi:10.1002/(sici)1097-0215(19991126)83:5<610::aid-ijc7>3.0.co;2-2

Cited by 55 publications

(39 citation statements)

References 18 publications

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“…Immunohistological data showed a high expression of p16 in normal epithelial cells of the prostate, while the expression decreased in prostate tumors. 41 Our findings have shown that LOH on cell-free DNA from PCa patients was less frequently detected in the paired blood plasma (5%) than in BM plasma (11%) which we obtained in parallel, suggesting that BL-LOH might be masked by the prevalence of normal DNA in blood 42 and that free tumor-specific DNA might accumulate in BM of PCa patients. Taback et al, 34 who reported the occurrence of tumor-specific DNA in BM plasma from 11 (23%) of 48 patients with breast cancer, also detected tumor-specific DNA with a higher frequency of LOH in BM than in blood plasma of these patients.…”

Section: Discussionmentioning

confidence: 53%

Detection of tumor‐specific DNA in blood and bone marrow plasma from patients with prostate cancer

Schwarzenbach

Chun

Lange

et al. 2007

Intl Journal of Cancer

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Tumor tissues, blood plasma and bone marrow (BM) aspirates of 57 prostate cancer patients (PCa) without clinical signs of overt metastases were assessed for LOH (loss of heterozygosity) by a PCRbased fluorescence microsatellite analysis, using a panel of 15 markers. Additionally, micrometastatic tumor cells in BM were monitored by an immunocytological cytokeratin assay. In total, 25 (44%), 32 (56%) and 41 (72%) of the patients had at least 1 LOH in their blood, BM and tumor samples, respectively. Among the informative cases, the frequency of LOH was highest in blood plasma for the markers D8S360 (18%) and D10S1765 (15%), and in BM plasma for THRB (24%) and D8S137 (22%). Comparison of blood plasma and BM with tumors showed discrepant results in 35% and 45% of patients, respectively. Whereas all LOHs at THRB in BM plasma were also detected in the autologous tumor tissues, LOHs at D6S474 and D11S898 in BM were not retrieved in the tumors. The comparison with established risk factors showed a correlation of borderline significance for LOH at D9S1748 in the BM aspirates (p 5 0.055) and a significant correlation in the tumor samples (p 5 0.004) with increasing pathologic Gleason scores. Interestingly, 22% of the PCa patients harbored tumor cells in their BM and tended (p 5 0.065) to have more frequent LOH (16%) in BM plasma compared to patients without tumor cells (9%). These data demonstrate, for the first time, the presence of free tumor-specific DNA in blood and BM of PCa patients and suggest a possible relationship to BM micrometastasis. ' 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 53%

Detection of tumor‐specific DNA in blood and bone marrow plasma from patients with prostate cancer

Schwarzenbach

Chun

Lange

et al. 2007

Intl Journal of Cancer

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“…The remainder of the coding sequence is encoded in exon 3, including the highly conserved RING domain. LOH in the chromosome 9p21 region has been described for several different malignancies, in many but not all cases related to loss of the tumor suppressor gene p16/CDKN2 (Kamb et al, 1994;Nobori et al, 1994;Puig et al, 1995;Devlin et al, 1996;Kim et al, 1997;Perinchery et al, 1999;Pollock et al, 2001). To evaluate LOH of the TOPORS gene, matched pairs of normal and cancer tissue specimens from 16 colon cancer patients were analysed using single-nucleotide polymorphism (SNP) markers that spanned a 120-kb region.…”

Section: Analyses Of the Topors Gene In Normal And Malignant Colon Timentioning

confidence: 99%

The topoisomerase I- and p53-binding protein topors is differentially expressed in normal and malignant human tissues and may function as a tumor suppressor

et al. 2004

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Topors was identified recently as a human protein that binds to topoisomerase I and p53. Topors contains a highly conserved RING domain and localizes in promyelocytic leukemia nuclear bodies. Relatively little is known regarding topors expression patterns or function. We now demonstrate that topors mRNA and protein are widely expressed in normal human tissues. By contrast, topors mRNA and protein levels are decreased or undetectable in colon adenocarcinomas relative to normal colon tissue, and expression of the topors protein is not detectable in several colon cancer cell lines. The human TOPORS gene is located on chromosome 9p21, with loss of heterozygosity in this region frequently observed in several different malignancies. While we were unable to detect loss of heterozygosity of the TOPORS gene in 16 sporadic colon cancer cases, increased methylation of a CpG island in the TOPORS promoter was evident in colon adenocarcinoma specimens relative to matched normal tissues. Additional studies indicate that forced expression of topors inhibits cellular proliferation and is associated with an accumulation of cells in the G 0 /G 1 phase of the cell cycle. This effect is independent of the topors RING domain and maps to a C-terminal region of the protein. These results suggest that topors functions as a negative regulator of cell growth, and possibly as a tumor suppressor.

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“…Conventional cytogenetic studies of prostatic adenocarcinoma have revealed loss of the Y chromosome, trisomy of chromosome 7, del(7)(q22), del(8)(p21), del (10)(q24), and the appearance of double minutes (reviewed in Brothman et al, 1999). Loss of heterozygosity (LOH) analyses have shown frequent loss on chromosome arms 3p, 6q, 7q, 8p, 9p, 10pq, 13q, 16q, 17q, and 18q (Cooney et al, 1996a(Cooney et al, , 1996bCunningham et al, 1996;Dahiya et al, 1997;Gao et al, 1995;Gray et al, 1995;Latil et al, 1997;Li et al, 1999;Melamed et al, 1997;Perinchery et al, 1999;Saric et al, 1999;Takahashi et al, 1995;Ueda et al, 1997;Vocke et al, 1996). Furthermore, comparative genomic hybridization (CGH) analysis applied to a panel of both primary and recurrent tumors revealed losses of 8p and 13q in primary tumors in over 30% of cases, whereas recurrent tumors showed gains of 8q and of chromosomes X and 7, as well as loss of 8p, in over one-half of the cases (Visakorpi et al, 1995b).…”

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confidence: 99%

Identification of Genetic Markers for Prostatic Cancer Progression

Alers

Rochat

Krijtenburg

et al. 2000

Laboratory Investigation

164

126

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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...

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High frequency of deletion on chromosome 9p21 may harbor several tumor-suppressor genes in human prostate cancer

Cited by 55 publications

References 18 publications

Detection of tumor‐specific DNA in blood and bone marrow plasma from patients with prostate cancer

Detection of tumor‐specific DNA in blood and bone marrow plasma from patients with prostate cancer

The topoisomerase I- and p53-binding protein topors is differentially expressed in normal and malignant human tissues and may function as a tumor suppressor

Identification of Genetic Markers for Prostatic Cancer Progression

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