The relatively high frequency of p53 gene mutations in multiple and malignant phaeochromocytomas

Yoshimoto, Taichiro; Naruse, Mitsuhide; Zeng, Z.; Nishikawa, Tomotaro; Kasajima, T; Toma, Helena Keiko; Yamamori, Shunji; Matsumoto, Haruna; Tanabe, Akiyo; Naruse, Keishi; Demura, Hiroshi

doi:10.1677/joe.0.1590247

Cited by 35 publications

(28 citation statements)

References 19 publications

(16 reference statements)

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“…18,20 However, two Asian studies reported 83% (5/6) and 40% (4/10) p53 mutations, respectively. 10,21 The reason for the discrepancy between these two groups of studies is not known, but may be related to geographical factors. Alternatively, we cannot entirely exclude the fact that mutations are present in other parts of the p53 gene, but it is known that more than 95% of mutations occur in exons 5-8.…”

Section: Discussionmentioning

confidence: 99%

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

et al. 2008

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Genetic changes in the tumorigenesis of sporadic pheochromocytomas are poorly understood, and there are no good markers to discriminate benign from malignant pheochromocytomas. p53 is a tumor suppressor gene and aberrations in this gene are frequently found in many tumor types. The role of p53 in pheochromocytoma tumorigenesis is unclear, with some studies suggesting that p53 mutations can be used to discriminate benign from malignant pheochromocytomas while other studies do not find such an association. Because most of these investigations were hampered by small series of tumors and the use of varying methods, we have performed a comprehensive analysis of p53 aberrations in a large series of pheochromocytomas. Comparative genomic hybridization analysis of 31 benign and 20 malignant tumors showed loss of the p53 locus at chromosome 17p13.1 in 23/51 (45%) cases, and most of these results were confirmed by fluorescence in situ hybridization. Forty-three tumors, including the malignant tumors and the tumors with loss of the p53 locus, were analyzed for p53 mutations in exons 5-8, but none were found. Furthermore, p53 immunohistochemistry on 35 cases revealed strong nuclear p53 expression in only two pheochromocytoma metastases, all other tumors being negative. We conclude that, although there is frequent loss of the p53 locus on 17p, the p53 gene does not appear to play a major role in pheochromocytoma tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

et al. 2008

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“…In particular, cis-acting regulatory sequences (i.e., those portions of noncoding DNA that bind to transcription factors that activate or repress gene expression) seem to play a critical role in transcriptional regulation. In addition, p53 intronic changes have been detected by others in a variety of tumors, such as malignant pheochromocytomas (44) and the blast phase of chronic myeloid leukemia (45). In some tumors, intronic p53 mutations have been shown to alter cell functions, such as apoptosis and proliferation (46), and have been associated with stabilization of the p53 protein (44).…”

Section: Discussionmentioning

confidence: 99%

p53 Alterations and Protein Accumulation in Benign Breast Tissue and Breast Cancer Risk: A Cohort Study

Rohan

Hartwick

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Disruption of p53 gene function seems to have a pivotal role in carcinogenesis. p53 gene changes occur before the development of breast cancer and therefore might influence breast cancer risk. We investigated the association between p53 protein accumulation and p53 mutations detected in benign breast tissue and risk of subsequent breast cancer. We conducted a case-control study nested within the cohort of 4,888 women in the Canadian National Breast Screening Study who were diagnosed with biopsy-confirmed benign breast disease during active follow-up. Cases were women with benign breast disease who subsequently developed breast cancer; five controls were matched to each case. p53 protein accumulation was assessed immunohistochemically using sections of paraffin-embedded benign breast tissue from 104 cases and 385 controls; for 82 of these cases and 327 of the controls, DNA was successfully extracted from the breast tissue for p53 gene analysis using PCR-singlestrand conformation polymorphism/direct sequencing. p53 protein accumulation was associated with a 2-fold increase in risk of progression to breast cancer [adjusted odds ratio (OR), 2.16; 95% confidence interval (95% CI), 1.08-4.30], whereas p53 nucleotide changes overall were not associated with altered risk (adjusted OR, 1.22; 95% CI, 0.68-2.19); those with both p53 immunopositivity and a p53 nucleotide change had an OR (95% CI) of 3.20 (1.21-8.50). Nonpolymorphic intronic changes were associated with a 2.8-fold increase in risk (OR, 2.84; 95% CI, 1.09-7.41). The results of this study suggest that p53 protein accumulation and nonpolymorphic intronic changes in p53 are associated with increased risk of progression to breast cancer in women with benign breast disease. (Cancer Epidemiol Biomarkers Prev 2006;15(7):1316 -23)

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“…Conflicting results have been reported for DNA flow cytometry (13,31,32), overexpression of the proto-oncogene products c-erb B-2 and bcl-2 (a marker of apoptosis; 16,33,34), mutations in the tumor suppressor gene p53 and its product (14,33,35), elevated plasma neuropeptide Y levels (36, 37), elevated urinary dopamine levels reflecting an immature secretion pattern (27), and absence of S-100 sustentacular cells (16,17). Immunohistochemical staining for the cell adhesion molecule E-cadherin (14), the oncogene product of HER-2/neu (14), PCNA (a marker of proliferative activity; 13), somatic mutations in the RET proto-oncogene (17), and angiogenesis assessed by high microvascular count (15) seem to have no potential diagnostic utility in this tumor type.…”

Section: Discussionmentioning

confidence: 99%

“…The clones were linearized by appropriate restriction enzymes for in vitro transcription using Riboprobe System components from Promega (Madison, WI) and 35 S-UTP (10 mCi/mL, Amersham Pharmacia Biotech Inc, Piscataway, NJ) to form antisense-and senselabeled RNA probes. The probes, EMMPRIN (1.6 kb) and MMP-2 (1.2 kb), were then purified by ultrafiltration (Microcon 100; Amicon, Inc., Beverly, MA) and generated at a specific activity of 2.1-3.1 ϫ 10 6 cpm/ L and 1.4 -2.9 ϫ 10 6 cpm/ L, respectively.…”

Section: Mrna In Situ Hybridizationmentioning

confidence: 99%

KI-67 AND hTERT Expression Can Aid in the Distinction between Malignant and Benign Pheochromocytoma and Paraganglioma

et al. 2003

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The clinical and histopathological distinction between benign and malignant pheochromocytomas and paragangliomas is difficult, and reliable diagnostic markers are lacking. Here we have evaluated the prognostic value of human telomerase reverse transcriptase (hTERT) gene expression detected by reverse transcription PCR (RT-PCR); telomerase activity (TA) measured by TRAP (telomeric repeat amplification protocol) assay; immunohistochemical staining for Ki-67/MIB-1; and the mRNA expression of matrix metalloproteinase (MMP)-2 and EMMPRIN (extracellular matrix metalloproteinase inducer) analyzed by in situ hybridization in 32 primary pheochromocytomas or abdominal paragangliomas. hTERT was expressed in 7/11 malignant tumors (defined as presence of metastasis and/or extensive local invasion) as compared with in 2/21 benign tumors. All of the benign tumors showed <1% proliferative activity, as measured by Ki-67/MIB-1 staining. In all three patients with malignant tumors who developed metastases and/or invasive local recurrence during follow-up, the tumors were positive for either hTERT expression or Ki-67/MIB-1 immunoreactivity. TA was not a significant discriminator between benign and malignant tumors, and the value of EMMPRIN and MMP-2 as predictive markers was limited. In conclusion, the findings imply that the combined use of Ki-67/ MIB-1 and hTERT, in addition to histopathology, provides a highly specific tool to identify benign pheochromocytoma and abdominal paraganglioma cases that are not at risk of developing recurrent or metastatic disease.

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The relatively high frequency of p53 gene mutations in multiple and malignant phaeochromocytomas

Cited by 35 publications

References 19 publications

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

p53 Alterations and Protein Accumulation in Benign Breast Tissue and Breast Cancer Risk: A Cohort Study

KI-67 AND hTERT Expression Can Aid in the Distinction between Malignant and Benign Pheochromocytoma and Paraganglioma

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