Very frequent p53 mutations in metastatic prostate carcinoma and in matched primary tumors

Meyers, Frederick J.; Gumerlock, Paul H.; Gil, Sung; Borchers, Holger; Deitch, Arline D.; White, Ralph W. deVere

doi:10.1002/(sici)1097-0142(19981215)83:12<2534::aid-cncr19>3.0.co;2-v

Cited by 81 publications

(42 citation statements)

References 24 publications

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“…58 Moreover, some papers report a strong association between prostate cancer bone metastases and a high frequency of TP53 mutations. 2,59 In our study, no mutations were detected in metastatic tumors, but the number of metastatic cases was low. Meyers et al 59 performed PCR-SSCP and immunohistochemistry to detect somatic DNA alterations, but they only sequenced one case.…”

Section: Discussioncontrasting

confidence: 51%

“…Many authors have used immunohistochemistry to evaluate the TP53 gene mutation. 2,59 It is thought that some mutations generate an abnormal protein that is not adequately metabolized and accumulates in the nucleus, allowing its immunohistochemical detection. In any event, immunohistochemical overexpression does not necessarily indicate gene mutation, as the protein accumulation may result from abnormalities in other genes involved in TP53 regulation and metabolism.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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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

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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

et al. 2008

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“…Structural and functional alterations a ecting the androgen receptor or its signaling pathways are probably responsible for many of the biological and biochemical changes associated with the neoplastic transformation of prostate epithelial cells (Gottlieb et al, 1999;Jenster, 1999). Other genetic changes, such as mutations in oncogenes (Shen et al, 1995;Sun et al, 1997) and tumor suppressor genes (Brooks et al, 1996;Meyers et al, 1998;Whang et al, 1998) have been implicated in the multistep sequence of prostate carcinogenesis (Whang et al, 1998), and alterations in genes such as HPC1 (Smith et al, 1996) and BRCA1 (Fan et al, 1998) have been evaluated for their implication in familial forms of prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

PTOV1, a novel protein overexpressed in prostate cancer containing a new class of protein homology blocks

et al. 2001

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In a search for molecular markers of progression in prostate cancer by means of di erential display, we have identi®ed a new gene, which we have designated PTOV1. Semiquantitative RT ± PCR has established that nine out of 11 tumors overexpress PTOV1 at levels signi®cantly higher than benign prostatic hyperplasia or normal prostate tissue. The human PTOV1 protein consists almost entirely of two repeated blocks of homology of 151 and 147 amino acids, joined by a short linker peptide, and is encoded by a 12-exon gene localized in chromosome 19q13.3. A Drosophila melanogaster PTOV1 homolog also contains two tandemly arranged PTOV blocks. A second gene, PTOV2, was identi®ed in humans and Drosophila, coding for proteins with a single PTOV homology block and unrelated amino-and carboxyl-terminal extensions. A 1.8-Kb PTOV1 transcript was detected abundantly in normal human brain, heart, skeletal muscle, kidney and liver, and at low levels in normal prostate. Immunocytochemical analysis and expression of chimeric GFP-PTOV1 proteins in cultured cells showed a predominantly perinuclear localization of PTOV1. In normal prostate tissue and in prostate adenomas, PTOV1 was undetectable or expressed at low levels, whereas nine out of 11 prostate adenocarcinomas showed a strong immunoreactivity, with a focal distribution in areas of carcinoma and prostatic intraepithelial neoplasia. Therefore, PTOV1 is a previously unknown gene, overexpressed in early and late stages of prostate cancer. The PTOV homology block represents a new class of conserved sequence blocks present in human, rodent and¯y proteins. Oncogene (2001) 20, 1455 ± 1464.

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“…The histologic examination of tissue for HER-2 expression as a basis for treatment with trastuzumab is one such example. 67,68 Differential gene alterations (e.g., phosphatase and tensin homolog (PTEN) 69 and p53 70 ), apoptotic pathway imbalances (e.g., BAX and bcl-2 71 ), differences in protein expression of interleukin-6, 72 insulin-like growth factor binding proteins (IGFBPs), 73 and neuropeptides, 74 and activation of various signal transduction pathways and molecules all impact androgen-independent prostate carcinoma progression to a variable degree in different patients. Longitudinal availability of tissue specimens for analysis and the stratification of patients at different points in their disease state will direct targeted therapies.…”

Section: Future Clinical Trialsmentioning

confidence: 99%

Society of Urologic Oncology position statement: Redefining the management of hormone‐refractory prostate carcinoma

Chang

Benson

Campbell

et al. 2004

Cancer

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Very frequent p53 mutations in metastatic prostate carcinoma and in matched primary tumors

Cited by 81 publications

References 24 publications

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

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

PTOV1, a novel protein overexpressed in prostate cancer containing a new class of protein homology blocks

Society of Urologic Oncology position statement: Redefining the management of hormone‐refractory prostate carcinoma

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