TP53-Associated Pediatric Malignancies

Pinto, Emília M.; Ribeiro, Raul C.; Figueiredo, Bonald C.; Zambetti, Gerard P.

doi:10.1177/1947601911409745

Cited by 40 publications

(20 citation statements)

References 69 publications

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“…The tumor was derived from a child who carried a germline TP53 G245C mutation, which expresses a structurally altered, inactive tumor suppressor protein (24–26). Loss of heterozygosity with selection against the wild-type TP53 allele is common in pediatric ACC (4, 27) and was observed in both the primary and xenograft tumors. Affymetrix analysis also revealed similar patterns of gene expression between the primary and xenograft tumors, including the overexpression of IGF-2, and these profiles are consistent with ACC (figure 2 and supplementary figure 2) (18).…”

Section: Discussionmentioning

confidence: 99%

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Establishment and Characterization of the First Pediatric Adrenocortical Carcinoma Xenograft Model Identifies Topotecan as a Potential Chemotherapeutic Agent

Pinto

Morton

Rodríguez‐Galindo

et al. 2013

Clinical Cancer Research

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Purpose Pediatric adrenocortical carcinoma (ACC) is a rare and highly aggressive malignancy. Conventional chemotherapeutic agents have shown limited utility and are largely ineffective in treating children with advanced ACC. The lack of cell lines and animal models of pediatric ACC has hampered the development of new therapies. Here we report the establishment of the first pediatric ACC xenograft model and the characterization of its sensitivity to selected chemotherapeutic agents. Experimental Design A tumor from an 11-year-old boy with previously untreated ACC was established as a subcutaneous xenograft in immunocompromised CB17 scid−/− mice. The patient harbored a germline TP53 G245C mutation, and the primary tumor showed loss of heterozygosity with retention of the mutated TP53 allele. Histopathology, DNA fingerprinting, gene expression profiling, and biochemical analyses of the xenograft were performed and compared with the primary tumor and normal adrenal cortex. The second endpoint was to assess the preliminary antitumor activity of selected chemotherapeutic agents. Results The xenograft maintained the histopathologic and molecular features of the primary tumor. Screening the xenograft for drug responsiveness showed cisplatin had a potent antitumor effect. However, etoposide, doxorubicin, and a panel of other common cancer drugs had little or no antitumor activity, with the exception of topotecan, which was found to significantly inhibit tumor growth. Consistent with these preclinical findings, topotecan as a single agent in a child with relapsed ACC resulted in disease stabilization. Conclusion Our study established a novel TP53-associated pediatric ACC xenograft and identified topotecan as a potentially effective agent for treating children with this disease.

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Section: Discussionmentioning

confidence: 99%

“…ACT is more common among children who harbor germline TP53 mutations (e.g., Li-Fraumeni syndrome) or who have other tumor-prone constitutional syndromes (4). Children with ACT usually develop symptoms related to increased production of androgens, corticosteroids, aldosterone, and estrogens, and approximately 80% present with virilization.…”

Section: Introductionmentioning

confidence: 99%

Establishment and Characterization of the First Pediatric Adrenocortical Carcinoma Xenograft Model Identifies Topotecan as a Potential Chemotherapeutic Agent

Pinto

Morton

Rodríguez‐Galindo

et al. 2013

Clinical Cancer Research

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“…Germline TP53 mutation is markedly associated with pediatric ACT by promoting chromosomal instability (4). It has been proposed that loss of the normal inhibitory role of TP53 protein in the cell cycle is associated with the development of ACC (27).…”

Section: Discussionmentioning

confidence: 99%

Common module analysis reveals prospective targets and mechanisms of pediatric adrenocortical adenoma and carcinoma

Kulshrestha

Sethi

2017

Oncol Lett

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Abstract. Pediatric adrenocortical carcinoma and adrenocortical adenoma are two rare diseases affecting children. Molecular analyses were performed to identify commonalities in gene expression between the diseases. Differentially expressed genes were identified for the pediatric adrenocortical adenoma and carcinoma tissues, as compared with normal tissues, using the expression dataset. Protein-protein interaction (PPI) networks were constructed for adenoma and carcinoma disease models, and common modules among the diseases were identified. A total of two common modules with 14 nodes and 20 nodes were revealed among the adenoma and carcinoma networks, respectively. Genes of the common modules were also identified to be the common hub genes of the disease models. Enrichment of the genes of the common modules suggested associations with steroid biosynthesis, the proteasome, cell cycle and metabolic pathways. Modularity, topological and functional analysis of the PPI networks revealed common modules among pediatric adenoma and carcinoma disease models, which provided insight into the underlying disease mechanisms and suggesting prospective targets for future study. IntroductionPediatric adrenocortical tumors (ACT) are a rare but aggressive endocrine malignancy accountable for ~0.2% of childhood cancer cases (1). ACTs comprise benign adenomas and highly malignant carcinomas whose pathogenesis remains incompletely understood (2). The majority of pediatric ACTs are functional, with symptoms of excessive androgen production, in comparison to adult ACT (1). Though histopathological demarcation between adenoma and carcinoma is complicated, 80-90% of pediatric ACTs are carcinomas (1). Complete surgical resection remains the only potent treatment for pediatric ACT (3).The elements responsible for sporadic pediatric ACT remain unknown, yet the resemblance of cases of ACT to cases with inherent susceptibility indicates a common method of tumorigenesis (4). Germline TP53 mutations (Li-Fraumeni syndrome) or genetic and/or epigenetic modifications affecting chromosome 11p15 (Beckwith-Wiedemann syndrome) are commonly associated with childhood ACT (4). Insulin-like growth factor 2 (IGF2) overexpression has been identified in pediatric adrenocortical adenoma and carcinoma. In addition, IGF1R mRNA levels have been demonstrated to be higher in pediatric adrenocortical carcinomas (ACC) (5). Carcinomas have been revealed to possess more chromosomal alterations when compared with adenomas (6). In a prior study, it was hypothesized that a number of genomic changes are responsible for progression from normal tissue, to adenoma to carcinoma (7).A considerable number of disease-associated genes have been identified by expression studies in previous years (8). In the present study, bioinformatics methodologies, such as protein-protein interaction (PPI) network analyses (9), that are based upon gene-encoded proteins interactions and gene module analysis have been utilized to investigate the underlying biological processes of progressing pedia...

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“…Trzeba zauważyć, że skutki aktywacji TP53 są złożone. Różnią się zarówno w zależności od typu komórki, jak i od siły oraz czasu trwania stresora na komórkę, a także od stopnia zniszczenia genomu [10,11]. Prawidłowe komórki po osiągnięciu odpowiedniej gęstości populacji zaprzestają podziałów, co określa się mianem hamowania kontaktowego.…”

Section: Brak Reakcji Na Sygnał Zahamowania Wzrostuunclassified

“…It should be noted that the effects of TP53 activation are complex. They differ in terms of the type of cell, strength, duration of the stresssor action on the cell as well as the degree of genomic damage [10,11]. After reaching the appropriate population density, normal cells cease to divide, which is called contact inhibition.…”

Section: No Response To Growth Arrest Signalmentioning

confidence: 99%

Molecular mechanisms of neoplasia

Derkacz

Komosińska-Vassev

2017

Ann. Acad. Med. Siles.

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The evolution of normal cells into neoplastic cells involves many stages. This paper describes six characteristics of tumour cells: maintenance of cell division-promoting signals, resistance to exogenous growth inhibitors, avoidance of apoptosis, acquisition of the ability to undergo an infinite number of divisions, induction of angiogenesis as well as activation of the ability to invade and metastasise. The listed and described characteristics of tumor cells are associated with genomic instability and the production of inflammation. Genomic instability protes the formation of a diverse pool of cells, and the accumulation of traits of tumor cells leads to inflammation. The progress of science has enabled the addition of two further features acquired by cells during the process of neoplasia -modification of cellular metabolism and avoidance of recognition by the immune system. K E Y W O R D Sangiogenesis, apoptosis, genomic instability, neoplastic progression ST R ES ZCZ E NI EEwolucja komórki prawidłowej w nowotworową obejmuje wiele etapów. W pracy opisano sześć cech charakteryzują-cych komórki nowotworowe: utrzymanie sygnałów stymulujących podziały komórkowe, oporność na egzogenne inhibitory wzrostu, unikanie apoptozy, nabywanie zdolności do nieskończonej liczby podziałów, indukcję angiogenezy oraz aktywację zdolności do inwazji i przerzutowania. U podłoża wymienionych cech leży nie tylko niestabilność genomu promująca wytworzenie zróżnicowanej genetycznie puli komórek, ale także stan zapalny, który wymaga wystąpienia wielu cech charakterystycznych dla komórek nowotworowych. Postęp badań pozwolił dodać dwie kolejne cechy nabyte przez komórki w czasie nowotworzenia -modyfikację metabolizmu komórkowego oraz unikanie rozpoznania przez system immunologiczny.

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TP53-Associated Pediatric Malignancies

Cited by 40 publications

References 69 publications

Establishment and Characterization of the First Pediatric Adrenocortical Carcinoma Xenograft Model Identifies Topotecan as a Potential Chemotherapeutic Agent

Establishment and Characterization of the First Pediatric Adrenocortical Carcinoma Xenograft Model Identifies Topotecan as a Potential Chemotherapeutic Agent

Common module analysis reveals prospective targets and mechanisms of pediatric adrenocortical adenoma and carcinoma

Molecular mechanisms of neoplasia

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