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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumors are believed to arise as a result of an accumulation of mutations in critical genes involved in the control of cell proliferation. Thyroid neoplasms represent a good model for studying the role of these mutations in epithelial cell multistep carcinogenesis because they comprise a broad spectrum of lesions with different degrees of malignancy. Recent reports have described the involvement of specific genetic alterations in different types of thyroid neoplasms. Papillary carcinomas are characterized by the activation of the receptor tyrosine kinases RET and TRK-A proto-oncogenes. Ras point mutations are frequently observed in tumors with follicular histology and a high prevalence of p53 point mutations have been found in anaplastic carcinomas. A definition of molecular defects characterizing thyroid tumors will be helpful in establishing sensitive and specific detection strategies and, in addition, to define genetic and environmental factors important for their pathogenesis.
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PMID:Molecular defects in thyroid carcinomas: role of the RET oncogene in thyroid neoplastic transformation. 758 78

The three known mechanisms of cellular transformation and oncogenesis include mutations in proto-oncogenes, inactivation of both copies of a tumor suppressor gene, and defects in DNA mismatch repair genes. Examples of each are included to substantiate the importance of understanding these mechanisms. RET is a proto-oncogene that is fundamental to the pathogenesis, and in the current era, molecular diagnosis of MEN 2 syndromes. TP53 is a tumor suppressor gene that is mutated in individuals with Li-Fraumeni syndrome. CDKN2 is a tumor suppressor gene that is mutated in pancreatic cancers and is associated with a poorer prognosis and the development of melanoma. MSH2 is a mismatch repair gene that is important in the pathogenesis of HNPCC and Muir-Torre syndrome. Altered gene function such as loss of DCC in colon cancers may affect cell adhesion properties and promote metastases. As we begin to better define and understand the mechanisms of neoplasia, we will be able to improve current diagnosis and treatment.
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PMID:Advances in molecular genetics. 904 82

The evolution of cancer is a multistep phenomenon, and multiple cellular genetic lesions are involved in the emergence of the malignant neoplasm. Several early events have been implicated in the neoplastic transformation of thyrocytes, and recent reports have described the involvement of specific genetic alterations in different types of thyroid neoplasms: ras point mutations are frequently observed in tumours with follicular histology, gsp-the mutated form of the alpha subunit of the Gs-protein-is encountered in up to 73% of papillary or follicular thyroid carcinomas, and a high prevalence of p53 point mutations has been found in anaplastic thyroid carcinomas but not in differentiated follicular tumours. More recent studies revealed that the RET proto-oncogene is involved in the oncogenesis of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) by activation of its tyrosine kinase either by point mutation or rearrangement. In this review the most important recently published data on alterations of the RET proto-oncogene in heritable and sporadic MTCs and in PTCs will be summarized. Emphasis will be directed to the pathophysiological mechanisms of tumour initiation, the indications and limitations of DNA testing, and the clinical implications of identified RET defects in thyroid lesions.
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PMID:The RET proto-oncogene in medullary and papillary thyroid carcinoma. Molecular features, pathophysiology and clinical implications. 924 27

We studied a family in which thyroid neoplasms appeared to occur through genetic inheritance. Six blood relations, including the two probands, had thyroid carcinoma, and six others had benign thyroid tumors. When both parents had a thyroid neoplasm, their children frequently had thyroid neoplasms; this was confirmed through two generations of this family. To clarify the mechanism of inheritance, we performed chromosomal analysis, Southern blot analysis of three variable number of tandem repeats markers and HLA typing on two probands, and examined their RET proto-oncogenes, and p53 and RB tumor suppressor genes. We could not find any positive data on genetic analysis, although our data were limited. In conclusion, we studied a family in which thyroid neoplasms have occurred partly through genetic inheritance, although environmental factors may have influenced the occurrence of thyroid diseases. A search for a predisposing gene, using the microsatellite technique, is required to clarify the gentic factors involved.
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PMID:Clinical and genetic analysis of an inherited case of thyroid adenoma/cancer. 936 3

Thyroid carcinomas of an additional series of 34 children exposed to radioactive fall-out after the Chernobyl reactor accident were analysed for mutations in the H-, K- and N-RAS and the p53 gene. Allele-specific oligonucleotide hybridization, single-strand conformation polymorphism (SSCP) and direct sequencing did not disclose mutations in codons 12, 13 and 61 of RAS genes nor mutations in exons 5, 7 and 8 of p53. Considering the recently reported high prevalence of RET rearrangements of the PTC3 type in childhood tumours after Chernobyl (Klugbauer et al, 1995, Oncogene 11: 2459-2467), it follows that RET rearrangements are the most relevant molecular aberration in these radiation-induced tumours. RAS or p53 mutations do not play a role in childhood thyroid carcinogenesis after Chernobyl.
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PMID:Absence of RAS and p53 mutations in thyroid carcinomas of children after Chernobyl in contrast to adult thyroid tumours. 952 40

The molecular genetics of endocrine tumours is an area of great interest, due to the heterogeneity of endocrine tumour types, the association of hormone over-production in some cases, and the wide variation in tumour behaviour. Genes implicated fall into functional categories such as oncogenes, in which mutations tend to cause activation, and tumour suppressor genes, in which mutations lead to loss of function. Oncogenes include the receptor tyrosine kinases such as RET, signal transduction proteins and other molecules such as cell cycle regulators and nuclear proteins. Tumour suppressor genes include cell cycle regulators such as p53 and other molecules such as the MEN 1 gene. Loss of heterozygosity studies help in the initial localisation of the latter. Endocrine tumours, as with other tumours, develop as a result of a combination of genetic events, and in the paediatric age group they often occur in the setting of familial cancer syndromes. In this review we analyse the main genetic lesions which have been described in endocrine tumours. There has been an explosion of knowledge in the last 5 years including the identification of the causative genes for MEN 2 and most recently for MEN 1. Characterisation of such genes also aids in the study of somatic mutations in sporadic versions of the same tumour types as occur in the familial syndromes. Identification of a genetic predisposition to a certain tumour has management implications that are still to be clarified in most cases, although in the case of MEN 2 the guidelines for prophylactic thyroidectomy are generally well accepted.
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PMID:The molecular genetics of endocrine tumours. 964 36

Epidemiological studies have revealed a connection between thyroid carcinogenesis and a history of radiation. The molecular mechanisms involved are not well understood. It has been claimed that RAS, p53 or GSP mutations and RET or TRK rearrangements might play a role in adult thyroid tumors. In childhood, the thyroid gland is particularly sensitive to ionizing radiation. The reactor accident in Chernobyl provided a unique chance to study molecular genetic aberrations in a cohort of children who developed papillary thyroid carcinomas after a short latency time after exposure to high doses of radioactive iodine isotopes. According to the concepts of molecular genetic epidemiology, exposure to a specific type of irradiation might result in a typical molecular lesion. Childhood papillary thyroid tumors after Chernobyl exhibit a high prevalence of RET rearrangement as almost the only molecular alteration. The majority showed RET/PTC3 (i.e., ELE/RET rearrangements), including several subtypes. Less frequently, RET/PTC1 (i.e., H4/RET rearrangements), and a novel type (RET/PTC5, i.e., RFG5/RET) were observed. Proof of reciprocal transcripts suggests that a balanced intrachromosomal inversion leads to this rearrangement. Breakpoint analyses revealed short homologous nucleotide stretches at the fusion points. In all types of rearrangement, the RET tyrosine kinase domain becomes controlled by 5' fused regulatory sequences of ubiquitously expressed genes that display coiled-coil regions with dimerization potential. Oncogenic activation of RET is apparently due to ligand-independent constitutive ectopic RET tyrosine kinase activity. The analysis of this cohort of children with radiation-induced thyroid tumors after Chernobyl provides insights into typical molecular aberrations in relation to a specific mode of environmental exposure and may serve as a paradigm for molecular genetic epidemiology.
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PMID:Molecular genetics of childhood papillary thyroid carcinomas after irradiation: high prevalence of RET rearrangement. 1002 5

Mutations are defined as stable and irreversible modifications of the normal genetic message due to small changes in the number or type of bases, or to large modifications of the genome such as deletions, insertions or chromosome rearrangements. These lesions are due to either polymerase errors during normal DNA replication or unrepaired DNA lesions, which will give rise to mutations through a mutagenic pathway. The molecular process leading to mutagenesis depends largely on the type of DNA lesions. Base modifications, such as 8-oxo-guanine or thymine glycol, both induced by ionizing radiations (IR), are readily replicated leading to direct mutations, usually base-pair substitutions. The 8-oxo-G gives rise predominantly to G to T transversions, the type of mutations found in ras or p53 gene from IR-induced tumors. Bulky adducts produced by chemical carcinogens or UV-irradiation are usually repaired by the nucleotide excision repair (NER) pathway which is able to detect structural distortion in the normal double-strand DNA backbone. These lesions represent a blockage to DNA and RNA polymerases as well as some signal for p53 accumulation in the damaged cell. In the absence of repair, these lesions could be eventually replicated owing to the induction of specific proteins at least in bacteria during the SOS process. The precise nature of the error-prone replication across an unexcised DNA lesion in the template is not fully understood in detailed biochemical terms, in mammalian cells. IR basically produce a very large number of DNA lesions from unique base modifications to single- or double-strand breaks and even complex DNA lesions due to the passage of very high energy particles or to a local re-emission of numerous radicals. The breakage of the double-helix is a difficult lesion to repair. Either it will result in cell death or, after an incorrect recombinational pathway, it will induce frameshifts, large deletions or chromosomal rearrangements. Most of the IR-induced mutations are recessive ones, requiring therefore a second genetic event in order to exhibit any harmful effect and a long latency period before the development of a radiation-induced tumor. The fact that IR essentially induced deletions and chromosomal translocations renders very difficult the use of the p53 gene as a marker for mutation analysis. In agreement with the type of lesions induced by IR, it is interesting to point out that the presence has been observed, in a vast majority of radiation-induced papillary thyroid carcinomas (PTC), of an activated ret proto-oncogene originated by the fusion of the tyrosine kinase 3' domain of this gene with the 5' domain of four different genes. These ret chimeric genes which are due to intra- or inter-chromosomal translocations, were called RET/PTC1 to PTC5. The RET/PTC rearrangements were found in PTC from children contaminated by the Chernobyl fall-out as well as in tumours from patients with a history of therapeutic external radiation, with a frequency of 60-84%. This frequency was only 15% in 'spontaneous' PTC. The type of ret chimeric gene predominantly originated by the accidental or therapeutic IR was different. Indeed, PTC1 was present in 75% of the tumours linked to a therapeutic radiation and PTC3 in 75% of the Chernobyl ones. The other forms of RET/PTC were observed in only a minority of the post-Chernobyl PTC (< 20%). The difference in the frequency of PTC1 and PTC3 in both types of PTC, is statistically significant (P < 10(-5), Fischer's exact test). In two of the post-therapeutic radiation PTC, RET/PTC1 and PTC3 were simultaneously present. A PTC1 gene was also observed in 45% of the adenomas appearing after therapeutic radiation. The long-period of latency between exposure to IR and the appearance of thyroid tumours is probably due to the conversion of a heterozygote genotype of IR-induced mutations to a homozygote one. It will be interesting to use this time lag in accidental or therapeutic-irradiated p
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PMID:Mechanisms of mutagenesis in mammalian cells. Application to human thyroid tumours. 1019 66

MEN1 is a syndrome of parathyroid adenomas, gastrinomas, prolactinomas, and other endocrine tumors. Collagenomas and facial angiofibromas are newly recognized but common skin expressions. Many tumors in MEN1 are benign; however, many entero-pancreatic neuroendocrine tumors and foregut carcinoid tumors are malignant. MEN1 is thus the expression of a cancer gene but without available prevention or cure for malignancy. Hereditary (as compared to sporadic) endocrine tumors show early onset age and multiplicity, because each cell of the body has "one hit" by inheritance. Multiple neoplasia syndromes with endocrine tumor(s) all include nonendocrine components; their known defective genes seem mainly to disturb cell accumulation. Hereditary neoplasia/hyperplasia of one endocrine tissue reflects a defect that is tissue selective and directed at cell secretion. Though the hereditary endocrine neoplasias are rare, most of their identified genes also contribute to common sporadic endocrine neoplasms. Hereditary tumors may be caused by activation of an oncogene (e.g., RET) or, more often, by inactivation of a tumor suppressor gene (e.g., P53, MEN1). Recently, MEN1 was identified by positional cloning. This strategy included narrowing the gene candidate interval, identifying many or all genes in that interval, and testing the newly identified candidate genes for mutation in MEN1 cases. MEN1 was identified because it showed mutation in 14 of 15 MEN1 cases. NIH testing showed germline MEN1 mutations in 47 of 50 MEN1 index cases and in seven of eight cases with sporadic MEN1. Despite proven capacity to find germline MEN1 mutation, NIH testing found no MEN1 mutation among five families with isolated hyperparathyroidism, suggesting that this often arises from mutation of other gene(s). Analogous studies in Japan found that familial isolated pituitary tumors also did not show MEN1 germline mutation. MEN1 mutation testing can now be considered for cases of MEN1 and its phenocopies and for asymptomatic members of families with known MEN1 mutation. Germline MEN1 testing does not have the urgency of RET testing in MEN2a and 2b, as MEN1 testing does not commonly lead to an important intervention. Somatic MEN1 mutation was found in sporadic tumors: parathyroid adenoma (21%), gastrinoma (33%), insulinoma (17%), and bronchial carcinoid (36%). For each of these, MEN1 was the known gene most frequently mutated. MEN1 has a widely expressed mRNA that encodes a protein (menin) of 610 amino acids. The protein sequence is not informative about domains or functions. The protein was mainly nuclear. Menin binds to JunD, an AP-1 transcription factor, inhibiting JunD's activation of transcription. Most of the germline and somatic MEN1 mutations predict truncation of menin, a likely destructive change. Inactivating MEN1 mutations in germline and in sporadic neoplasms support prior predictions that MEN1 is a tumor suppressor gene. Germline MEN1 mutation underlies all or most cases of MEN1 (familial or sporadic). Somatic MEN1 mutation is the most common gene mutation in many sporadic endocrine tumor types.
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PMID:Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias. 1054 85

The increase in thyroid carcinoma post-Chernobyl has been largely confined to a specific subtype of papillary carcinoma (solid/follicular). This subtype is observed predominantly in children under 10 in unirradiated populations, but maintains a high frequency in those aged 10-15 from those areas exposed to fallout from the Chernobyl accident. The aim of this study was to link morphology with molecular biology. We examined 106 papillary carcinomas from children under the age of 15 at operation. All were examined for rearrangements of the RET oncogene by reverse transcription polymerase chain reaction (RT-PCR); a subset of these cases were also examined for mutations of the three ras oncogenes, exon 10 of the thyroid stimulating hormone receptor, associated more usually with a follicular rather than papillary morphology, and exons 5, 6, 7 and 8 of the p53 gene, commonly involved in undifferentiated thyroid carcinoma. Rearrangements of the REToncogene were found in 44% of papillary carcinomas in which we studied fresh material; none of the tumours examined showed mutation in any of the other genes. The two rearrangements resulting from inversion of part of chromosome 10 (PTC1 and PTC3) accounted for the majority of RET rearrangements identified, with PTC1 being associated with papillary carcinomas of the classic and diffuse sclerosing variants and PTC3 with the solid/follicular variant.
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PMID:Gene rearrangement and Chernobyl related thyroid cancers. 1064 83


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