The p53 mutation “gradient effect” and its clinical implications

Zambetti, Gerard P.

doi:10.1002/jcp.21217

Cited by 67 publications

(49 citation statements)

References 41 publications

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“…However, to further test the hypothesis, allelic differences for the MDM4 haplotype were explored in a different tumor type and by using a different experimental design. As functional p53 pathway polymorphisms and somatic genetic alterations of p53 pathway genes have also been shown to affect ovarian cancer (30,43,44), potential allelic differences in the age of diagnosis were tested in case studies of both familial and sporadic ovarian cancer in Caucasian populations of non-AJ ethnicity.…”

Section: Resultsmentioning

confidence: 99%

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

Atwal

Kirchhoff

Bond

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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A large body of evidence strongly suggests that the p53 tumor suppressor pathway is central in reducing cancer frequency in vertebrates. The protein product of the haploinsufficient mouse double minute 2 (MDM2) oncogene binds to and inhibits the p53 protein. Recent studies of human genetic variants in p53 and MDM2 have shown that single nucleotide polymorphisms (SNPs) can affect p53 signaling, confer cancer risk, and suggest that the pathway is under evolutionary selective pressure ( 1 – 4 ). In this report, we analyze the haplotype structure of MDM4, a structural homolog of MDM2, in several different human populations. Unusual patterns of linkage disequilibrium (LD) in the haplotype distribution of MDM4 indicate the presence of candidate SNPs that may also modify the efficacy of the p53 pathway. Association studies in 5 different patient populations reveal that these SNPs in MDM4 confer an increased risk for, or early onset of, human breast and ovarian cancers in Ashkenazi Jewish and European cohorts, respectively. This report not only implicates MDM4 as a key regulator of tumorigenesis in the human breast and ovary, but also exploits for the first time evolutionary driven linkage disequilibrium as a means to select SNPs of p53 pathway genes that might be clinically relevant.

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Section: Resultsmentioning

confidence: 99%

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

Atwal

Kirchhoff

Bond

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…2,49 The vast majority of TP53 mutations are missense point mutations 50 that affect the DNA-binding domain. 51 Many authors have used immunohistochemistry to evaluate the TP53 gene status, because some mutations could lead to p53 protein accumulation and immunohistochemical detection. Nevertheless, immunohistochemical overexpression does not necessarily indicate gene mutation.…”

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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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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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“…Naturally occurring sequence variations within p53 (SNP, codon72, rs1042522, C/G) in human populations cause measurable perturbations of p53 function (9). Importantly, polymorphisms and somatic genetic alterations of genes encoding p53 and its regulators have been shown to affect ovarian cancer (10,11). For instance, a single nucleotide polymorphism (SNP) in the P2 promoter of MDM2, one of the key regulators of p53 (12), was recently associated with an earlier age of tumor onset in estrogen receptor (ER) overexpressing ovarian carcinomas (6).…”

Section: Introductionmentioning

confidence: 99%

An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity

et al. 2010

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Overexpression of MDM4 (also known as MDMX or HDMX) is thought to promote tumorigenesis by decreasing p53 tumor suppressor function. Even modest decrease in Mdm4 levels affects tumorigenesis in mice, suggesting that genetic variants of MDM4 might have similar effects in humans. We sequenced the MDM4 gene in a series of ovarian cancer cell lines and carcinomas to identify mutations and/or single nucleotide polymorphisms (SNPs). We identified an SNP (SNP34091) in the 3 0 -UTR of MDM4 that creates a putative target site for hsa-miR-191, a microRNA that is highly expressed in normal and tumor tissues. Biochemical evidence supports specific miR-191-dependent regulation of the MDM4-C, but not MDM4-A, variant. Consistently, the A-allele was associated with statistically significant increased expression of MDM4 mRNA and protein levels in ovarian carcinomas. Importantly, the wild-type genotype (A/A) is more frequent (57.8% vs. 42.2% for A/C and C/C, respectively) in patients with high-grade carcinomas than in patients with low-grade carcinomas (47.2% vs. 52.5% for A/A and A/C þ C/C, respectively). Moreover, A/A patients who do not express the estrogen receptor had a 4.2-fold [95% confidence interval (CI) ¼ 1.2-13.5; P ¼ 0.02] increased risk of recurrence and 5.5-fold (95% CI ¼ 1.5-20.5; P ¼ 0.01) increased risk of tumor-related death. Unexpectedly, the frequency of p53 mutations was not significantly lower in A/A patients. We conclude that acquisition of an illegitimate miR-191 target site causes downregulation of MDM4 expression, thereby significantly delaying ovarian carcinoma progression and tumor-related death. Importantly, these effects appear to be, at least partly, independent of p53. Cancer Res; 70(23); 9641-9. Ó2010 AACR.

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The p53 mutation “gradient effect” and its clinical implications

Cited by 67 publications

References 41 publications

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

Altered tumor formation and evolutionary selection of genetic variants in the human MDM4 oncogene

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

An Illegitimate microRNA Target Site within the 3′ UTR of MDM4 Affects Ovarian Cancer Progression and Chemosensitivity

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