<i>P53</i> gene mutation in an atypical corticotroph adenoma with Cushing's disease

Kawashima, Sachiko–Tsukamoto; Usui, Takeshi; Sendo, Toshiaki; Iogawa, Hitomi; Hagiwara, Hanae; Tamanaha, Tamiko; Tagami, Tetsuya; Naruse, Mitsuhide; Hojo, Masato; Takahashi, June A.; Shimatsu, Akira

doi:10.1111/j.1365-2265.2008.03404.x

Cited by 49 publications

(28 citation statements)

References 9 publications

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“…Also, mutation of p53 gene in ACTHsecreting pituitary adenoma is an extremely rare event. So far only L145R mutation has been reported in an atypical corticotroph adenoma [15]. Our finding along with the report of L145R mutation indicate that the role of disruption of p53 signaling in the genesis of aggressive pituitary tumors needs to be verified more carefully.…”

Section: Before Radiotherapymentioning

confidence: 49%

Possible role of a radiation-induced p53 mutation in a Nelson’s syndrome patient with a fatal outcome

et al. 2009

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Nelson's syndrome (NS) is characterized by the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for the treatment of Cushing's disease. Such corticotroph macroadenomas respond poorly to currently available therapeutic options which include surgery, radiotherapy and chemotherapy. P53 protein accumulation may be detected by immunohistochemistry in pituitary corticotroph adenomas and it has been suggested that it might be causally related to tumor development. Wild type P53 protein plays an important role in the cellular response to ionizing radiation and other DNA damaging agents and is mutated in many human tumors. In this study we report an adult male patient with NS who underwent both transsphenoidal and transcranial pituitary surgeries, conventional and stereotaxic radiotherapy and brachytherapy. Despite of the efforts to control tumor mass and growth, this macroadenoma displayed relentless growth and aggressive behavior. DNA extracted from the first two surgical samples, as well as DNA from peripheral blood leukocytes disclosed normal p53 sequence. DNA extracted from tumor samples obtained at surgeries performed after pituitary irradiation carried a somatic heterozygous mutation, consisting of a deletion of four cytosines between nucleotides 12,144-12,149 in exon 4 of the p53 gene. This frameshift mutation creates a stop codon in exon 4 excluding the expression of a functional protein from the defective allele. These data demonstrate a possible association between the P53 protein loss of function induced by radiotherapy and the aggressive course of the disease in this patient.

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Section: Before Radiotherapymentioning

confidence: 49%

Possible role of a radiation-induced p53 mutation in a Nelson’s syndrome patient with a fatal outcome

et al. 2009

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“…Mutations in proto-oncogenes like KRAS, RET, PTTG and c-MYC and in tumor suppressors like RB1 are very rarely reported in corticotrophinomas (10). Mutations in the p53 gene (TP53) are extremely rare and were found only in atypical corticotroph (i.e., aggressive) tumors and carcinomas (11,12). CD is rarely seen in the context of genetic syndromes like multiple endocrine neoplasia MEN1 (MEN1 encoding menin), MEN4 (CDKN1B encoding p27/KIP1), McCuneAlbright syndrome (GNAS oncogene encoding the stimulatory G protein Gsa) and never in Carney complex (PRKAR1A) (13,14,15).…”

Section: Genetic Events In CDmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.

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“…Numerous previous studies attempted to gain insight into the molecular mechanisms underlying the development of Cushing's disease, but only a few rare mutations have been reported (3)(4)(5)(6)(7)(8). Recently, an exhaustive exome-wide screening has led us to identify somatic mutations in the ubiquitin-specific protease 8 (USP8; Ensembl: ENSG00000138592) in six of 17 patients (9).…”

mentioning

confidence: 97%