<i>p53</i> mutations in matched primary and metastatic human tumors

Peller, Shoshana; Halevy, Ariel; Slutzki, S; Kopilova, Yulia; Rotter, Varda

doi:10.1002/mc.2940130306

Cited by 28 publications

(17 citation statements)

References 28 publications

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“…This finding is in contrast to colonic adenocarcinomas that typically demonstrate higher rates of mutation for TP53 and reactivity to p53. 5,16,17,19,20 I I I ANI I I ANI I I ANI I 0/8 REAH2 ANI ANI I ANI LOH I I I I LOH I 2/8 REAH3 LOH ANI ANI I LOH LOH LOH I I LOH LOH 6/9 REAH4 ANI ANI LOH I ANI I ANI I I LOH LOH 3/7 REAH5 NI A...…”

Section: Discussionmentioning

confidence: 98%

Tumor Suppressor Gene Alterations in Respiratory Epithelial Adenomatoid Hamartoma (REAH)

Ozolek

Hunt

2006

American Journal of Surgical Pathology

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Respiratory epithelial adenomatoid hamartoma (REAH) is an unusual benign sinonasal glandular proliferation. REAH is not considered a neoplasm, although, no molecular evidence exists to support or refute this possibility. Microdissection of 10 cases of REAH, 9 cases of sinonasal adenocarcinoma (SNAC) and 10 cases of chronic sinusitis was performed. DNA was extracted and polymerase chain reaction performed using fluorescently labeled primers flanking known tumor suppressor genes on chromosomes 9p (CDKN2/p16), 11p (H-ras), 17p (p53), and 18q (DCC/DPC4). Polymerase chain reaction products were analyzed semiquantitatively by capillary electrophoresis. Allele ratios were calculated using the peak height from the shorter allele divided by the peak height from the longer allele. The loss of heterozygosity (LOH) ratio was calculated as the allele ratio from tumor tissue divided by the allele ratio from normal tissue. The fractional allelic loss (FAL) was calculated as the percentage of loci that harbored LOH divided by the number of loci that were informative. REAH demonstrated an intermediate FAL of 31% compared with SNAC (64%) and chronic sinusitis (2%). REAH and SNAC had the highest LOH for multiple loci located on 9p (p16) and 18q (DCC/DPC4). The molecular profile of REAH shows a mean FAL of 31%, which would be considered unusually high for a non-neoplastic entity. Appreciable allelic loss within REAH suggests the possibility that REAH may be a benign neoplasm rather than a hamartoma.

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Section: Discussionmentioning

confidence: 98%

Tumor Suppressor Gene Alterations in Respiratory Epithelial Adenomatoid Hamartoma (REAH)

Ozolek

Hunt

2006

American Journal of Surgical Pathology

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“…Abnormalities of p53 are frequently found in human breast cancer and have important clinical implications [3,[11][12][13]16,17,22]. A number of studies have shown that tumors lacking wild-type p53 are likely to have a relatively poor prognosis [3,23].…”

Section: Resultsmentioning

confidence: 99%

“…Work in a number of systems has suggested that the T AG protein disrupts the regulation of cellular growth by interacting with key nuclear proteins such as p53 and pRb, which normally function to regulate cell proliferation [8][9][10]. Mutations in the tumor suppressor gene p53 are known to occur in over 50% of human tumors, including metastatic breast cancers [11][12][13]. p53 mutations can occur at various stages in carcinogenesis and have various effects on its progression [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Reducedp53 dosage associated with mammary tumor metastases in C3(1)/TAG transgenic mice

et al. 1997

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Transgenic mice expressing the simian virus 40 large T-antigen (TAG) under the regulatory control of the rat prostatic steroid binding protein C3(1) gene develop mammary carcinomas (in females) and prostate carcinomas (in males). The development of carcinomas occurs several months after the appearance of dysplastic lesions, suggesting that TAG is necessary but insufficient for tumor formation and that other genetic events are involved in this process. TAG is known to bind to p53 and to result in its functional inactivation, which is believed to be a critical step in TAG-induced transformation. We investigated whether the TAG-p53 interaction is rate limiting in the development of phenotypic changes in these transgenic mice by crossing C3(1)/TAG transgenics with mice carrying null mutations of the p53 gene. TAG-expressing animals with a p53+/- genotype developed much more aggressive mammary tumors, as evidenced by increased numbers and size of metastases, than did TAG-expressing animals carrying two wild-type p53 alleles. While p53 was expressed in primary tumors, p53 expression appeared to be reduced or lost in many metastases in mice carrying either the p53+/+ or p53+/- genotypes. The tumorigenic process did not appear to be due to the loss of the second wild-type p53 allele or the gain of dominant oncogenic mutations in p53, as no mutations were detected in either primary or metastatic tumors by polymerase chain reaction--single-strand conformation polymorphism analyses. These findings suggest that despite the presence of TAG, p53 levels influence the characteristics of the late stages of mammary tumor growth and accelerate metastases. Functional loss of p53 and not p53 mutations participates in TAG-induced mammary carcinoma development and progression.

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“…9 The p53 gene exhibits several mutations both in coding and noncoding regions, namely single nucleotide polymorphisms (SNPs) in exon 4 at codon 72 10,11 and intron 6. 12 Ara et al 13 reported that the above two mutant varieties are functionally distinct from their wild type gene product because of inequalities in both their biological and biochemical properties.…”

Section: Introductionmentioning

confidence: 99%

ENU administration causes genomic instability along with single nucleotide polymorphisms in p53 during gliomagenesis: T11TS administration demonstrated in vivo apoptosis of these genetically altered tumor cells

Mukherjee

Ghosh²,

Ghosh³

et al. 2006

Cancer Biology & Therapy

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Advancement of molecular analysis of neoplastic cells demonstrated that multiple genetic changes are associated with the development of tumors. Cancer cell must exhibit a mutator phenotype, which is likely to be responsible for the genomic instability found in cancer tissues. The mutator phenotype, such as defective mismatch repair, is known to cause microsatellite instability, which is associated with certain cases of sporadic cancer. Previously many studies have been carried out to determine the relationship between microsatellite instability and human brain tumors. However information on genomic instability in the animal model of brain tumor is still very limited. In the present course of investigations we genetically characterized our ENU induced brain tumor animal model by using PCR based randomly amplified polymorphic DNA (RAPD) analysis and restriction fragment length polymorphism (RFLP) with three microsatellite probes. ENU induced tumors demonstrated genetic instability, including some microsatellite instability. As single nucleotide polymorphisms of the tumor suppressor gene p53 were associated with diverse types of human cancer, we examined the p53 gene of the tumor cells isolated from ENU induced brain tumor animal model, by PCR based RFLP method in p53 exon-2, -3 and -4. In these studies we showed that the restriction site of p53 exon-3 and 4 were mutated in ENU induced brain tumor indicating a genetic defect associated with ENU induced tumorigenesis. In the therapeutic part, we confirmed the anti-tumor property of T11TS/ S-LFA-3 in the ENU induced genetically altered cells. Histological evidences, cytotoxic study, PI-FACS cell-cycle analysis and TUNEL assay confirmed the apoptotic death of glioma cells by T11TS treatment in which p53 is mutated. From the present study we can conclude that ENU administration causes genomic instability along with mutations in p53 during the process of gliomagenesis. Whereas, T11TS/S-LFA3 demonstrated the potential to induce apoptosis of these tumor cells even when p53 is mutated and thus showed its immense potential to be an anti-neoplastic probe against p53 mutated diverse types of tumors.

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p53 mutations in matched primary and metastatic human tumors

Cited by 28 publications

References 28 publications

Tumor Suppressor Gene Alterations in Respiratory Epithelial Adenomatoid Hamartoma (REAH)

Tumor Suppressor Gene Alterations in Respiratory Epithelial Adenomatoid Hamartoma (REAH)

Reducedp53 dosage associated with mammary tumor metastases in C3(1)/TAG transgenic mice

ENU administration causes genomic instability along with single nucleotide polymorphisms in p53 during gliomagenesis: T11TS administration demonstrated in vivo apoptosis of these genetically altered tumor cells

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