Expression of p53 tumor suppressor gene in adenoid cystic and mucoepidermoid carcinomas of the salivary glands

Kiyoshima, Tamotsu; Shima, Kaori; Kobayashi, Ieyoshi; Matsuo, Keitaro; Okamura, Kazuhiko; Komatsu, Shuichi; Rasul, A. M.E.; Sakai, Hidetaka

doi:10.1016/s1368-8375(00)00083-x

Cited by 79 publications

(65 citation statements)

References 19 publications

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“…Papadaki et al 18 reported that mutations in the tumorsuppressor gene TP53 are not important in early events in the development of adenoid cystic carcinoma but they involved at later stages of tumor progression and they are, thus, important in recurrence of adenoid cystic carcinoma. By contrast, Kiyoshima et al 19 found infrequent mutations in TP53 in adenoid cystic carcinoma. It appears, therefore, mutation of TP53 does not necessarily play a critical role in the tumorigenesis of adenoid cystic carcinoma.…”

Section: Discussionmentioning

confidence: 86%

Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma

et al. 2004

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The Wnt signaling pathway is essential for normal development and organogenesis. However, inappropriate activation of Wnt signaling, which results in the nuclear translocation of b-catenin, is associated with the development of various types of neoplasm. In this study, we investigated possible mutations in the genes for components of this pathway, namely, CTNNB1 (the gene for b-catenin), AXIN1, and APC, in adenoid cystic carcinoma, by PCR, analysis of single-strand conformational polymorphism, and sequencing. Among a total of 20 cases of adenoid cystic carcinoma, seven cases (35%) were associated with mutations in one or more of these three components. A mutation in CTNNB1 was detected in one case. Five cases, including the case with a mutation in CTNNB1, were associated with missense mutations in AXIN1. An aberration in the mutation cluster region of APC was detected in two cases. Mutations trended to be detected more frequently in adenoid cystic carcinoma with solid growth pattern than that with tubular and cribriform growth pattern. In the cases in which we detected mutations, it is possible that the presence of the abnormal products of the mutated genes resulted in the inappropriate activation of the Wnt signaling pathway to tumorigenesis and the growth of adenoid cystic carcinoma.

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Section: Discussionmentioning

confidence: 86%

Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma

et al. 2004

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“…Weber and co-workers analyzed TP53 mutations by direct sequencing of exons 4-9 and detected mutations in 4/42 PA and 3/12 myoepitheliomas [14]. Despite the evidence that TP53 might be altered in SGN [10,13,14,16,17,18], we sequenced all of our samples and found only four missense mutations, one nonsense TP53 mutation and a very low frequency of LOH at the 17p 13.1 region in our subset of salivary tumor samples.…”

Section: Discussionmentioning

confidence: 69%

“…Previous papers reported positive immunoexpression of p53 protein [8,9], yet TP53 mutations seem to be infrequent events in pleomorphic adenomas (PA), adenoid cystic carcinomas (ACC), mucoepidermoid carcinomas (MEC) and carcinomas ex pleomorphic adenomas (CAexPA) [10,11,12,13,14]. These previous papers relied on different techniques (SSCP, for example, which misses mutations when compared to direct sequencing), and in some of them, sequencing was only performed on a few samples.…”

Section: Introductionmentioning

confidence: 99%

Assessment of TP53 mutations in benign and malignant salivary gland neoplasms

2012

Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology

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Despite advances in the understanding of the pathogenesis of salivary gland neoplasms (SGN), the molecular pathways associated with enhanced tumor growth and cell survival remain to be established. The aim of the present study was to investigate whether TP53 mutations are relevant to SGN pathogenesis and if they impact on p53 protein expression. The study included 18 benign and 18 malignant SGN samples. Two polymorphic microsatellite markers at the TP53 genetic locus were chosen to assess loss of heterozygosity (LOH) in the samples that had matched normal DNA. The TP53 exons 2-11 were amplified by PCR, and all of the products were sequenced. Reverse transcription-PCR of the TP53 open reading frame (ORF) was carried out in the samples that had fresh tissue available, and immunohistochemistry for the p53 protein was performed in all samples. TP53 LOH was only found in two pleomorphic adenomas. We found two missense mutations in exon 7 (one in a pleomorphic adenoma and the other in a polymorphous low grade adenocarcinoma), another in exon 8 (in a carcinoma ex pleomorphic adenoma) and a fourth missense mutation in exon 10 (in a mucoepidermoid carcinoma). In addition, a nonsense mutation was found in exon 8 of an adenoid cystic carcinoma. Several intronic and exonic SNPs were detected. Although almost all of the malignant samples were immunopositive for p53, approximately 37% of the benign samples were positive, including the sample harboring the missense mutation and one of the samples that showed LOH. The complete TP53 ORF could be amplified in all samples analyzed, including the IHC negative samples, the samples showing LOH and one sample displaying a missense mutation. In summary, our results show that TP53 mutations are not a frequent event in SGN and that p53 immunopositivity might not be associated with sequence mutations in SGN.

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“…However, unlike other carcinomas reported previously, ACC and MEC showed relatively low rates of alteration of p53 in the present study. Kiyoshima et al (2001) and Papadaki et al (1996) also reported low frequency of the alteration of p53 gene in ACC and MEC. Thus, the downregulation of 14-3-3 s in ACC might not be due to the inactivation of p53 pathway, and inactivation of 14-3-3 s by methylation may lead to impairment of some of the functions of p53 as a 'gatekeeper'.…”

Section: Discussionmentioning

confidence: 86%

“…These findings suggest that cell cyclerelated gene(s) at the G2 checkpoint might play important roles in the difference in radiosensitivity between these cancers, since the G2-residing cells are normally more sensitive to irradiation. However, alteration of G2 cell cycle regulators such as p53 is reported to be infrequent in SGCs (Papadaki et al, 1996;Tsubochi et al, 2000;Kiyoshima et al, 2001). Thus, it is possible that novel G2 cell cycle regulator(s) contribute to the different radiosensitivity in SGCs.…”

mentioning

confidence: 99%

Frequent downregulation of 14-3-3 σ protein and hypermethylation of 14-3-3 σ gene in salivary gland adenoid cystic carcinoma

Uchida

Almofti

et al. 2004

Br J Cancer

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14-3-3 σ , a target gene of the p53 tumour suppressor protein, has been shown to regulate the cell cycle at the G2/M checkpoint. Recent studies have demonstrated that 14-3-3 σ is downregulated by hypermethylation of the CpG island in several types of cancer. In this study, we investigated the expression and methylation status of 14-3-3 σ in human salivary gland adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC). Immunohistochemical analysis revealed that the positive expression rate of 14-3-3 σ in ACC (one out of 14) was markedly lower than that in MEC (ten out of 10). Since most of the ACCs carried the wild-type p53 protein, downregulation of 14-3-3 σ in ACC may not be due to the dysfunction of p53 pathway. Microdissection–methylation-specific PCR revealed that frequent hypermethylation of the 14-3-3 σ gene was observed in ACC when compared to that in MEC. In cultured-ACC cells, we confirmed the downregulation of 14-3-3 σ via hemimethylation of the gene by sequencing analysis after sodium bisulphite treatment. Furthermore, re-expression of 14-3-3 σ in the ACC cells was induced by the treatment with DNA demethylating agent, 5-aza-2′-deoxycytidine. Irradiation apparently induced the enhanced expression of 14-3-3 σ and G2/M arrest in normal salivary gland cells; however, in the ACC cells, neither induction of 14-3-3 σ nor G2/M arrest was induced by irradiation. These results suggest that downregulation of 14-3-3 σ might play critical roles in the neoplastic development and radiosensitivity of ACC.

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Expression of p53 tumor suppressor gene in adenoid cystic and mucoepidermoid carcinomas of the salivary glands

Cited by 79 publications

References 19 publications

Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma

Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma

Assessment of TP53 mutations in benign and malignant salivary gland neoplasms

Frequent downregulation of 14-3-3 σ protein and hypermethylation of 14-3-3 σ gene in salivary gland adenoid cystic carcinoma

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