Evidence for a prostate cancer susceptibility locus on the X chromosome.

Xu, Jianfeng; Meyers, Deborah A.; Freije, Diha; Isaacs, Sarah D.; Wiley, Kathy E.; Nusskern, Deborah; Ewing, Charles M.; Wilkens, Eric P.; Bujnovszky, Piroska; Bova, G. Steven; Walsh, Patrick C.; Isaacs, William B.; Schleutker, Johanna; Matikainen, Mika; Tammela, Teuvo L.J.; Visakorpi, Tapio; Kallioniemi, Olli; Berry, Rebecca; Schaid, Daniel J.; French, Amy J.; McDonnell, Shannon K.; Schroeder, Jennifer J.; Blute, Michael L.; Thibodeau, Stephen N.; Grönberg, Henrik; Emanuelsson, Monika; Damber, Jan Erik; Bergh, Anders; Jonsson, Björn; Smith, Jeffrey R.; Bailey-Wilson, Joan E.; Carpten, John D.; Stephan, Dietrich A.; Gillanders, Elizabeth M.; Amundson, I.; Kainu, Tommi; Freas-Lutz, Diana; Baffoe-Bonnie, Agnes; Aucken, A. Van; Sood, Raman; Collins, Francis S.; Brownstein, Michael J.; Trent, Jeffrey M.

doi:10.1038/2477

Cited by 565 publications

(88 citation statements)

References 21 publications

(4 reference statements)

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“…This region is also reported to harbor a gene involved in PCa susceptibility (Xu et al, 1998). ZNF185 mRNA expression was detected in several normal human tissues by Northern blot analysis, and was most abundant in the prostate.…”

Section: Introductionmentioning

confidence: 94%

ZNF185, an actin–cytoskeleton-associated growth inhibitory LIM protein in prostate cancer

2006

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We have recently identified ZNF185 as a gene that is downregulated in prostate cancer (PCa), in part via epigenetic alteration, and maybe associated with disease progression. In this study, we cloned the ZNF185 cDNA from normal human prostate tissues and investigated its biological function. We show that ZNF185 is a novel actin-cytoskeleton-associated Lin-l 1, Isl-1 and Mec-3 (LIM) domain-containing protein that localizes to F-actin structures, and is enriched at focal adhesions. We find that the NH 2 -terminal region, which we designate the actintargeting domain, facilitates ZNF185 binding to actin in vitro and is both necessary and sufficient to mediate actin-cytoskeleton targeting of ZNF185, whereas the LIM domain, which is localized in the COOH-terminus is dispensable for this phenomenon. Interestingly, ectopic expression of full-length ZNF185, but not a mutant lacking the actin-targeting domain, could suppress proliferation and anchorage-independent growth of PCa cells. Together, our data suggest that ZNF185 may function as a tumor-suppressor protein by associating with the actincytoskeleton.

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Section: Introductionmentioning

confidence: 94%

ZNF185, an actin–cytoskeleton-associated growth inhibitory LIM protein in prostate cancer

2006

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“…Similar findings have been reported in literature (Bubendorf et al, 1999;Cher et al, 1996;Visakorpi et al, 1995a;1995b). The observation that gain of the whole X chromosome was the most recurrent abnormality of this chromosomes suggests that also other genes on chromosome X, possibly the recently identified second cancer susceptibility locus on Xq27-q28 (Xu et al, 1998), might be of importance for the progression of prostate cancer.…”

Section: Amplificationsmentioning

confidence: 99%

Identification of Genetic Markers for Prostatic Cancer Progression

Alers

Rochat

Krijtenburg

et al. 2000

Laboratory Investigation

163

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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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“…Six prostate cancer susceptibility loci (HPC1 at 1q24-25 (Smith et al, 1996), PCAP at 1q42-43 (Berthon et al, 1998), HPCX at Xq27-28 (Xu et al, 1998), CAPB at 1p36 (Gibbs et al, 1999), HPC20 at 20q13 (Berry et al, 2000) and HPC2 at 17p12 (Tavtigian et al, 2001)) and two candidate susceptibility genes (HPC2/ELAC2 at 17q (Tavtigian et al, 2001) and RNASEL at 1q24-25 ) have been reported.…”

mentioning

confidence: 99%