p53 tetramerization domain mutations: germline R342X and R342P, and somatic R337G identified in pediatric patients with Li–Fraumeni syndrome and a child with adrenocortical carcinoma

Fiszer-Maliszewska, Ł; Kazanowska, Bernarda; Padzik, Joanna

doi:10.1007/s10689-009-9284-2

Cited by 8 publications

(8 citation statements)

References 22 publications

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“…For example, tetramerization of p53 is essential for its binding to DNA . Mutations in the p53 tetramerization domain have been reported in patients with Li–Fraumeni syndrome, a rare disease presented as early cancer onset …”

Section: Discussionmentioning

confidence: 99%

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Integrating expression‐related SNPs into genome‐wide gene‐ and pathway‐based analyses identified novel lung cancer susceptibility genes

Wang

Zhu

et al. 2017

Intl Journal of Cancer

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Traditional pathway analysis map single nucleotide polymorphisms (SNPs) to genes according to physical position, which lacks sufficient biological bases. Here, we incorporated genetics of gene expression into gene- and pathway-based analysis to identify genes and pathways associated with lung cancer risk. We identified expression-related SNPs (eSNPs) in lung tissues and integrated these eSNPs into three lung cancer genome-wide association studies (GWASs), including 12,843 lung cancer cases and 12,639 controls. We used SKAT-C for gene-based analysis, and conditional analysis to identify independent eSNPs of each gene. ARTP algorithm was used for pathway analysis. A total of 374,382 eSNPs in the GWAS datasets survived quality control, which were mapped to 5,084 genes and 2,752 pathways. In the gene-based analysis, nine genes showed significant associations with lung cancer risk. Among them, TP63 (3q28), RP11-650L12.2 (15q25.1) and CHRNA5 (15q25.1) were located in known lung cancer susceptibility loci. We also validated two newly identified susceptibility loci (RNASET2 and AL133458.1 in 6q27, and MPZL3 in 11q23.3). Besides, DVL3 (3q27.1), RP11-522I20.3 (9q21.32) and CCDC116 (22q11.21) were identified as novel lung cancer susceptibility genes. Pathway analysis showed that pathways involved in protein structure, the Notch signaling pathway and the nicotinic acetylcholine receptor-related pathways were associated with lung cancer risk. Combing eSNPs, gene- and pathway-based analysis identifies novel lung cancer susceptibility genes, which serves as a powerful approach to decipher biological mechanisms underlying GWAS findings.

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Section: Discussionmentioning

confidence: 99%

“…39 Mutations in the p53 tetramerization domain have been reported in patients with Li-Fraumeni syndrome, a rare disease presented as early cancer onset. 40 MPZL3 (myelin protein zero-like 3) acts downstream of several known transcriptional regulators, including p63. It is essential for normal epidermal differentiation.…”

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 99%

Integrating expression‐related SNPs into genome‐wide gene‐ and pathway‐based analyses identified novel lung cancer susceptibility genes

Wang

Zhu

et al. 2017

Intl Journal of Cancer

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“…In this family pediatric neoplasms occurred, namely a synovial sarcoma at the age of 8 and an osteosarcoma at 12 years of age in one individual. In the study of Fiszer-Maliszewska et al [16] it was assumed that the p.Arg342Pro mutation was causally related to the Li-Fraumeni phenotype, but co-segregation of mutation and disease could not be shown because of lack of family members available for testing. In our study, we succeeded to extract and analyze old genomic DNA from a blood typing bedside test of the index patient's mother who had died 29 years ago of bilateral breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“…These mutations hit the DNAbinding domain (DBD). Meanwhile, however, several in vitro studies [12][13][14][15] and some clinical reports [16][17][18] have also shown that mutations in the tetramerization domain (TD) of p53 may have a destructive effect on protein functionality and are of pathological relevance.…”

Section: Introductionmentioning

confidence: 99%

Further evidence for pathogenicity of the TP53 tetramerization domain mutation p.Arg342Pro in Li–Fraumeni syndrome

et al. 2014

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Li-Fraumeni syndrome (LFS) is a rare genetic disease with a highly significant predisposition to multiple early-onset neoplasms. These neoplasms include adrenocortical carcinoma, sarcoma, leukemia and CNS tumors in children and sarcoma, breast cancer and lung cancer in adults. LFS is inherited in an autosomal dominant manner. In most patients germline mutations in the tumor suppressor gene TP53 are found. As the majority of known mutations affect the DNA-binding domain of the p53 protein, there are only a few case reports showing the clinical presentation of mutations outside of this mutational hotspot. Here we present a family with a typical LFS pedigree with patients suffering from early-onset lung cancer, bilateral breast cancer and osteosarcoma. TP53 sequence analysis of the index patient revealed the germline mutation c.1025G > C in a heterozygous state, resulting in an amino acid exchange from arginine to proline (p.Arg342Pro) in the tetramerization domain of p53. Using DNA from an old bedside blood typing test, the same mutation was found in the mother of the index patient, who had died of breast cancer 29 years ago. In conclusion, we provide evidence for the co-segregation of a TP53 tetramerization domain mutation and cancer phenotypes, but also report pre-symptomatic mutation carriers within the family. We review published recommendations for clinical management and surveillance of high-risk members in Li-Fraumeni kindreds.

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“…Essa síndrome familiar parece estar associada principalmente a mutações germinativas no gene TP53 em 70% dos pacientes (46). Diversas mutações neste gene, incluindo as mutações p.R342X, p.R342P e p.R337G, também foram encontradas em crianças com TAC associadas à síndrome de Li-Fraumeni (47).…”

Section: Bases Moleculares Dos Tumores Adrenocorticaisunclassified

Tumores adrenocorticais na criança: da abordagem clínica à avaliação molecular

Antonini

Colli²,

Ferro

et al. 2011

Arq Bras Endocrinol Metab

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sumárioTumores do córtex adrenal (TCA) são mais frequentes em crianças, mas podem ocorrer em qualquer faixa etária. São classificados como funcionantes, não funcionantes (predominam no adulto), e mistos. O diagnóstico é baseado na avaliação clínica, hormonal e exames de imagem. Em crianças, o método de escolha para diferenciar entre benigno ou maligno é a classificação baseada no estadiamento do tumor. Alguns marcadores moleculares merecem destaque: além de mutações inativadoras no gene supressor tumoral TP53, há evidências de envolvimento do IGF2 em 90% de TAC malignos, e mutações no éxon 3 do gene CTNNB1 foram encontradas em 6% dos TAC pediátricos. Além disso, microRNAs podem atuar como reguladores negativos da expressão gênica e participar da tumorigênese adrenocortical. Métodos para análise da expressão gênica permitem identificar TCA com prognóstico bom ou ruim, e espera-se que esses estudos possam facilitar o desenvolvimento de drogas para tratar pacientes de acordo com as vias de sinalização específicas que estiverem alteradas. Arq Bras Endocrinol Metab. 2011;55(8):599-606 Descritores Tumor do córtex adrenal; doenças da adrenal; fatores de crescimento; proteína supressora de tumor P53; biologia molecular summArY Adrenocortical tumors (ACT) are more frequent during childhood, but they can appear at any age. ACTs can be classified in functioning, nonfunctioning (mainly observed in adults) and mixed. The diagnosis is based on clinical, biochemical findings and imaging. In children, in order to classify ACT as benign or malignant, tumor staging classification is recommended. Regarding molecular markers some studies should be taken into account: besides TP53 mutations, previous studies have also provided evidences of IGF2 involvement in 90% of the malignant ACT. Mutations altering exon 3 of CTNNB1 gene have been found in 6% of childhood ACTs. In addition, microRNAs can act as negative regulators of gene expression by targeting mRNA controlling cell growth, differentiation and apoptosis and have been implicated in adrenal tumorigenesis. High-throughput methods to analyze genome-wide expression have been developed over the last decade and identified a subset of tumors with good or poor prognosis. In the future, these studies can provide the basis of specific drug development, which can treat patients according to specific altered signaling pathway. Arq Bras Endocrinol Metab. 2011;55(8):599-606 Keywords Adrenal cortex tumor; adrenal gland diseases; molecular biology growth factors; tumor suppressor protein P53 iNTroDuÇÃo O s tumores adrenocorticais (TAC) apresentam incidência bimodal, sendo mais comuns nos primeiros cinco anos de vida e entre a 4ª e 5ª décadas de vida. Em todas as faixas etárias esses tumores são mais frequentes no sexo feminino (1,2). Sua incidência varia de acordo com a região geográfica, sendo dez a quinze vezes mais elevada no Sul e Sudeste do Brasil, onde ocorrem apro-

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p53 tetramerization domain mutations: germline R342X and R342P, and somatic R337G identified in pediatric patients with Li–Fraumeni syndrome and a child with adrenocortical carcinoma

Cited by 8 publications

References 22 publications

Integrating expression‐related SNPs into genome‐wide gene‐ and pathway‐based analyses identified novel lung cancer susceptibility genes

Integrating expression‐related SNPs into genome‐wide gene‐ and pathway‐based analyses identified novel lung cancer susceptibility genes

Further evidence for pathogenicity of the TP53 tetramerization domain mutation p.Arg342Pro in Li–Fraumeni syndrome

Tumores adrenocorticais na criança: da abordagem clínica à avaliação molecular

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