Overexpression of the tumour suppressor gene p53 is not implicated in neuroendocrine tumour carcinogenesis

Wang, Da-Gong; Johnston, C.F.; Anderson, Neil; Sloan, James M.; Buchanan, K. D.

doi:10.1002/path.1711750406

Cited by 56 publications

(23 citation statements)

References 23 publications

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“…In contrast, we could not detect any abnormal immunostaining of p53 in five benign solitary phaeochromocytoma specimens without p53 gene mutations. These results agree with the report of Wang et al (1995) that showed no abnormal p53 immunostaining in 24 phaeochromocytoma specimens. The results of PCR-SSCP followed by direct DNA sequencing and immunohistochemistry demonstrated p53 gene mutations or intronic sequence alterations associated with abnormal accumulation of p53 protein phaeochromocytoma tissues from multiple and malignant cases.…”

Section: P53 Mutations In Adrenal Tumours · T Yoshimoto and Others 251supporting

confidence: 93%

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

Yoshimoto¹,

Naruse²,

Zeng³

et al. 1998

Journal of Endocrinology

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To explore the clinical significance of p53 in the pathogenesis of adrenal neoplasms, we investigated the incidence of p53 gene mutations in functioning human adrenal tumours using the polymerase chain reactionsingle strand conformation polymorphism (PCR-SSCP) technique to screen p53 exons 4 to 9. We examined 29 adrenocortical adenomas (primary aldosteronism, n=17; Cushing's syndrome, n=12, all benign), and 33 phaeochromocytomas (benign solitary, n=18; benign multiple, n=5; malignant, n=10) in Japanese and Chinese patients. PCR-SSCP did not show any abnormal band-shifts in any of the adrenocortical adenoma and benign solitary phaeochromocytoma tissues. In contrast, six phaeochromocytoma tissues (two cases benign multiple, four cases malignant) showed PCR-SSCP band-shifts. Subsequent DNA sequencing analysis of the shifted bands revealed six cases with nine mutations or intronic sequence alterations: three cases contained sequence alterations within intronic regions, three cases with silent mutation (sequence alteration in codon without amino acid alteration), and three cases contained missense mutations (one case each in exons 5, 6 and 9). Immunohistochemical staining demonstrated that two of three cases with missense mutations and one case with an intronic sequence alteration over-expressed p53 protein in tumour cell nuclei. We observed no association between p53 gene mutation and p21/WAF1/ Cip-1 expression. The relatively high incidence of p53 gene mutations or intronic sequence alteration in multiple and malignant phaeochromocytomas, but not in benign solitary cases, suggests that p53 mutation could play some role in the pathogenesis of multiple and/or malignant phaeochromocytomas.

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Section: P53 Mutations In Adrenal Tumours · T Yoshimoto and Others 251supporting

confidence: 93%

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

Yoshimoto¹,

Naruse²,

Zeng³

et al. 1998

Journal of Endocrinology

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“…A rationale for such investigations comes from studies in mice with p53 mutations who develop PETs (Harvey et al 1995). Nevertheless, most studies found no mutations of P53 and/or no overexpression of the mutated protein in human PETs (Evers et al 1994, Wang et al 1995, Bartz et al 1996, Pavelic et al 1996, Moore et al 2001b. These data suggest that findings of LOH at 17q13 may be related to other unknown TSGs.…”

Section: Genetic Alterations Of Oncogenes and Tsgsmentioning

confidence: 94%

Molecular pathology and genetics of pancreatic endocrine tumours

Capurso¹,

Festa²,

Valente³

et al. 2012

Journal of Molecular Endocrinology

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Pancreatic neuroendocrine tumours (PETs) are the second most frequent pancreatic neoplasms. Their poor chemosensitivity, high rate of metastatic disease and relatively long survival make PETs an ideal field to be explored for novel therapies based on specific molecular changes. PETs are generally sporadic but can also arise within hereditary syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1 and tuberous sclerosis complex, which represent a model for sporadic cases too. Among allelic imbalances, main genomic changes involve gain of 17q, 7q and 20q and loss of 11q, 6q and 11p, which identify regions of putative candidate oncogenes or tumour suppressor genes (TSGs), respectively, sometime with potential prognostic significance. Overexpression of Src-like kinases and cyclin D1 (CCND1) oncogene has been described. As for TSGs, P53 (TP53), DPC4/SMAD4 and RB (RB1) are not implicated in PET tumorigenesis, while for p16INK4a (CDKN2A), TIMP3, RASSF1A and hMLH1, more data are available, suggesting a role for methylation as a silencing mechanism. In the last decade, gene expression profile studies, analysis of microRNAs and, more recently, large-scale mutational analysis have highlighted commonly altered molecular pathways in the pathology of PETs. The roles of the mammalian target of rapamycin pathway, and its connection with Src kinases, and the activity of a number of tyrosine kinase receptors seem to be pivotal, as confirmed by the results of recent clinical trials with targeted agents. Mutations of DAXX and ATRX are common and related to altered telomeres but not to prognosis.

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“…Studies have shown that overexpression of p53 in neuroendocrine tumors, including medullary carcinomas of the thyroid, is rare. 22,23 In contrast, it has been suggested that p53, which has been shown to be diffusely positive in three laryngeal moderately differentiated neuroendocrine carcinomas, may play a role in the pathogenesis of this tumor, unlike other neuroendocrine tumors. 5 However, these findings have not been validated.…”

Section: Ttf-mentioning

confidence: 94%

Thyroid transcription factor-1, but not p53, is helpful in distinguishing moderately differentiated neuroendocrine carcinoma of the larynx from medullary carcinoma of the thyroid

2004

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Moderately differentiated neuroendocrine carcinoma/atypical carcinoid tumor is the most common nonsquamous malignancy in the larynx; however, due to morphologic overlap and calcitonin immunoreactivity, it can be difficult to distinguish from thyroid medullary carcinoma. Currently, low serum calcitonin is the most reliable means for distinguishing primary laryngeal moderately differentiated neuroendocrine carcinoma from metastatic medullary carcinoma. Thyroid transcription factor-1 (TTF-1) is positive in at least 80% of medullary carcinomas, but has not been evaluated in laryngeal moderately differentiated neuroendocrine carcinomas. Additionally, it has been suggested that p53 is positive in laryngeal moderately differentiated neuroendocrine carcinomas and negative in other neuroendocrine tumors, but this has not been validated. The purpose of this study was to determine if the immunohistochemical markers TTF-1 and p53 could be used to discriminate between laryngeal moderately differentiated neuroendocrine carcinomas and thyroid medullary carcinomas. Eight laryngeal moderately differentiated neuroendocrine carcinomas and 10 thyroid medullary carcinomas were identified from the archival files of the BWH and MGH Pathology Departments. Hematoxylin and eosin slides were reviewed, and immunohistochemistry was performed using antibodies to calcitonin, TTF-1, and p53. Calcitonin immunohistochemistry demonstrated immunoreactivity in 100% of laryngeal moderately differentiated neuroendocrine carcinomas (N ¼ 8) and 100% of thyroid medullary carcinomas (N ¼ 10). There was weak, focal immunoreactivity with TTF-1 in one of eight (13%) laryngeal moderately differentiated neuroendocrine carcinomas, whereas nine of ten (90%) medullary carcinomas were positive for TTF-1, with strong diffuse staining in seven of these cases (78%). p53 was positive in three of six (50%) laryngeal moderately differentiated neuroendocrine carcinomas, and three of ten (30%) medullary carcinomas. Our data demonstrate that immunoreactivity for TTF-1, but not calcitonin or p53, may be helpful in distinguishing laryngeal moderately differentiated neuroendocrine carcinoma and thyroid medullary carcinoma. In particular, diffuse and/or strong TTF-1 immunoreactivity favors a diagnosis of primary thyroid medullary carcinoma over laryngeal moderately differentiated neuroendocrine carcinoma. Keywords: carcinoid; neuroendocrine; medullary; larynx; thyroid; TTF-1; p53; calcitonin Moderately differentiated neuroendocrine carcinoma (atypical carcinoid tumor) is the most common nonsquamous malignancy in the larynx, metastasizing to regional lymph nodes, skin, subcutaneous tissue or distant sites in approximately 20-40% of cases. 1,2 Moderately differentiated neuroendocrine carcinomas of the larynx and medullary carcinomas of the thyroid demonstrate morphological overlap, and can be microscopically indistinguishable, particularly when presenting as a metastasis. Currently,

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Overexpression of the tumour suppressor gene p53 is not implicated in neuroendocrine tumour carcinogenesis

Cited by 56 publications

References 23 publications

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

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

Molecular pathology and genetics of pancreatic endocrine tumours

Thyroid transcription factor-1, but not p53, is helpful in distinguishing moderately differentiated neuroendocrine carcinoma of the larynx from medullary carcinoma of the thyroid

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