Unique substitution ofCHEK2 andTP53 mutations implicated in primary prostate tumors and cancer cell lines

Zheng, Liqin; Wang, Fengwei; Qian, Chiping; Neumann, Roxann M.; Cheville, John C.; Tindall, Donald J.; Liu, Wanguo

doi:10.1002/humu.9457

Cited by 18 publications

(16 citation statements)

References 16 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DU145 cells harbor mutations of codon 223 (CCT to CTT, Pro to Leu) and codon 274 (GTT to TTT, Val to Phe), also resulting in abnormal TP53 proteins (23,47). Although LNCaP cells express wild-type TP53, it harbors mutation of CHK2 at codon 1160 (C to A, Thr to Asn), leading to deficit of TP53 protein phosphorylation and activation (48). In prostate cancer tissue, about half harbor TP53 abnormalities.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA145 Targets BNIP3 and Suppresses Prostate Cancer Progression

et al. 2010

View full text Add to dashboard Cite

The putative tumor suppressor miR145 is transcriptionally regulated by TP53 and is downregulated in many tumors; however, its role in prostate cancer is unknown. On the other hand, BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) is overexpressed in various tumors, including prostate cancer, and may transcriptionally repress the apoptosis-inducing factor (AIF) gene. Although BNIP3 transcription is controlled by hypoxia-inducible factor 1α (also elevated in prostate cancer), we postulated the posttranscriptional regulation of BNIP3 by miR145 through bioinformatics analysis, and herein we experimentally showed that miR145 negatively regulated BNIP3 by targeting its 3′-untranslated region. Artificial overexpression of miR145 by using adenoviral vectors in prostate cancer PC-3 and DU145 cells significantly downregulated BNIP3, together with the upregulation of AIF, reduced cell growth, and increased cell death. Artificial overexpression of wild-type TP53 in PC-3 cells (which lack TP53 protein) and DU145 cells (in which mutated nonfunctioning TP53 is expressed) significantly upregulated miR145 expression with consequent effects on BNIP3 and cell behavior as with miR145 overexpression. Analysis of prostate cancer (n = 134) and benign prostate (n = 83) tissue sample showed significantly decreased miR145 and increased BNIP3 expression in prostate cancer (P < 0.001), particularly in those with tumor progression, and both molecular changes were associated with unfavorable outcome. Abnormalities of the miR145-BNIP3 pair as part of TP53-miR145-BNIP3-AIF network may play a major role in prostate cancer pathogenesis and progression. Cancer Res; 70(7); 2728-38. ©2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 99%

MicroRNA145 Targets BNIP3 and Suppresses Prostate Cancer Progression

et al. 2010

View full text Add to dashboard Cite

show abstract

“…A number of candidate genes have been reported that harbor somatic mutations in localized prostate cancer, including AR, TP53, KLF6, EPHB2, CHEK2, ZFHX3 (formerly known as ATBF1), and NCOA2 (Newmark et al 1992;Gottlieb et al 2004;Huusko et al 2004;Sun et al 2005;Dong 2006;Zheng et al 2006;Agell et al 2008;Taylor et al 2010). However, there are limited reports of somatic coding mutations in metastatic tumors.…”

mentioning

confidence: 99%

Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors

et al. 2010

View full text Add to dashboard Cite

Advanced prostate cancer can progress to systemic metastatic tumors, which are generally androgen insensitive and ultimately lethal. Here, we report a comprehensive genomic survey for somatic events in systemic metastatic prostate tumors using both high-resolution copy number analysis and targeted mutational survey of 3508 exons from 577 cancerrelated genes using next generation sequencing. Focal homozygous deletions were detected at 8p22, 10q23.31, 13q13.1, 13q14.11, and 13q14.12. Key genes mapping within these deleted regions include PTEN, BRCA2, C13ORF15, and SIAH3. Focal high-level amplifications were detected at 5p13.2-p12, 14q21.1, 7q22.1, and Xq12. Key amplified genes mapping within these regions include SKP2, FOXA1, and AR. Furthermore, targeted mutational analysis of normal-tumor pairs has identified somatic mutations in genes known to be associated with prostate cancer including AR and TP53, but has also revealed novel somatic point mutations in genes including MTOR, BRCA2, ARHGEF12, and CHD5. Finally, in one patient where multiple independent metastatic tumors were available, we show common and divergent somatic alterations that occur at both the copy number and point mutation level, supporting a model for a common clonal progenitor with metastatic tumor-specific divergence. Our study represents a deep genomic analysis of advanced metastatic prostate tumors and has revealed candidate somatic alterations, possibly contributing to lethal prostate cancer.

show abstract

“…52 It has also been reported that mutations in TP53 and CHEK2, a gene activated in response to various DNA-damaging agents, could be mutually exclusive in 25% of prostate tumors. 53 From all these studies, it is obvious that, although KLF6 and TP53 are important in controlling the cell cycle, their involvement in the pathogenesis of prostate cancer is still controversial and uncertain. Thus, the main goal of the present study has been to elucidate the real frequency of KLF6 and TP53 mutations in a large group of prostate cancer samples classified by stage and Gleason grade and performing more than one round of PCR and sequencing, in order to avoid artifactual mutations and other methodological problems often encountered in formalin-fixed, paraffin-embedded (FFPE) samples.…”

mentioning

confidence: 99%

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

et al. 2008

View full text Add to dashboard Cite

Krü ppel-like factor 6 (KLF6) has been reported to act as a tumor suppressor gene involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. Many studies suggest that KLF6 is inactivated by allelic loss and somatic mutation. However, there is a high variability in the reported frequency of mutations (from 1 to 55%). TP53 also regulates the cell cycle through the activation of p21. In prostate cancer, the reported frequency of TP53 mutations ranges from 3 to 42%. In all these reports, there is a considerable degree of methodological heterogeneity. Our aim was to determine the frequency of KLF6 and TP53 mutations in a welldefined group of prostate tumors with different stages and Gleason grades. The four exons of KLF6 and exons 4-9 of TP53 were studied in 103 cases, including 90 formalin-fixed, paraffin-embedded (FFPE) and 13 frozen samples. All tumors were analyzed through PCR and direct sequencing. All changes found were confirmed by a second independent PCR and sequencing reaction. For KLF6, mutation (E227G) was only detected in one tumor (1%) and for TP53, three different mutations (L130H, H214R, and Y234C) were detected in five tumors (5%). This low mutation index is in keeping with recent papers on the subject. Our study strongly supports the notion that KLF6 and TP53 mutations are not frequent events in prostate cancer. When using FFPE tissues, it is mandatory to perform at least two independent rounds of PCR and sequencing to confirm mutations and exclude Taq polymerase-induced artifacts. Two of these genes are Krü ppel-like factor 6 (KLF6) and TP53.KLF6 is a transcription factor that interacts with DNA through three zinc-fingers in its COOHterminal domain. KLF6 belongs to the KLF family, a family that is broadly involved in cell differentiation, development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. 5 It has been suggested that KLF6 could be involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. 6 This has been proven in several in vitro 5 and in vivo assays. 7 KLF6 is believed to regulate cancer development and progression through the downregulation of the c-Jun oncoprotein 8 and the activation of E-cadherin. 9 The reported frequency of KLF6 mutations in different types of human cancer varies in the different published studies. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In prostate cancer, four studies have analyzed the frequency of KLF6 mutations. 6,[30][31][32] In the first published study, Narla et al 6 showed a very high frequency, 55%, whereas in the following study, Chen et al 30 obtained a lower frequency, around 15%. The results of two recent reports provided frequencies of 0 and 1%. 31,32 It should be noted that there were considerable

show abstract

Unique substitution ofCHEK2 andTP53 mutations implicated in primary prostate tumors and cancer cell lines

Cited by 18 publications

References 16 publications

MicroRNA145 Targets BNIP3 and Suppresses Prostate Cancer Progression

MicroRNA145 Targets BNIP3 and Suppresses Prostate Cancer Progression

Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumors

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

Contact Info

Product

Resources

About