High incidence of low O6-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing's disease

Takeshita, Akira; Inoshita, Naoko; Taguchi, Manabu; Okuda, Chikao; Fukuhara, Noriaki; Oyama, Kenichi; Ohashi, Kenichi; Sendo, Toshiaki; Takeuchi, Yasuhiro; Yamada, Shozo

doi:10.1530/eje-09-0414

Cited by 64 publications

(67 citation statements)

References 23 publications

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“…These included tumor necrosis and hemorrhage, 15,23 tumor degenerative and cystic changes, 22 and tumor shrinkage. 2,10,11,14,[19][20][21]24 These changes could be observed as early as 2 months after the onset of temozolomide treatment.…”

Section: Morphologic Changesmentioning

confidence: 98%

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Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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Section: Morphologic Changesmentioning

confidence: 98%

“…To date, 6 patients with pituitary carcinomas have received treatment with temozolomide 10,[12][13][14]17,19,[23][24][25] (Table 1). These included 4 men and 2 women ages 26 to 77 years (mean, 49.8 years).…”

Section: Pituitary Carcinomasmentioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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“…In all cases, surgery was performed by the same surgeon (SY) who has experience with more than 2500 pituitary surgeries. Samples were examined by routine histological methods and immunohistochemical staining as previously described (21,22). They were classified as CCA when the percentage of Crooke's hyaline change in tumor cells was O50%, with the remaining tumor samples being considered as nonCrooke's cell adenoma (non-CCA) (1,21).…”

Section: Patientsmentioning

confidence: 99%

“…Samples were examined by routine histological methods and immunohistochemical staining as previously described (21,22). They were classified as CCA when the percentage of Crooke's hyaline change in tumor cells was O50%, with the remaining tumor samples being considered as nonCrooke's cell adenoma (non-CCA) (1,21). Sixteen tumor samples were identified as CCA from 209 samples (7.7%), and 15 out of 16 samples were available for RNA extraction.…”

Section: Patientsmentioning

confidence: 99%

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

Hayashi

Inoshita

Kawaguchi

et al. 2016

European Journal of Endocrinology

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139

156

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Context: Somatic mutations in the ubiquitin-specific peptidase USP8 gene were recently detected in one-to two-third(s) of corticotroph adenomas of Cushing's disease (CD). These mutations may lead to the deubiquitination of EGFR, thereby increasing EGFR signaling, which has been implicated in ACTH hypersecretion. Objective: Our objective was to determine the impact of USP8 mutations on the clinicopathological features of CD. Subjects and methods: USP8 mutations as well as clinicopathological characteristics were examined in 60 corticotroph adenomas including 15 Crooke's cell adenomas (CCAs), a rare histological variant presenting with generally aggressive behavior, using qRT-PCR and/or immunohistochemistry. Results: USP8 mutations were exclusively detected in women, except for one case, with a prevalence of 42.2% in non-CCA and 13.3% in CCA (overall 35%). Clinically well-behaved presentations including microadenoma and curative resection were more common in mutated cases. The expression of EGFR was not associated with the mutation status. In contrast, mutated tumors expressed significantly higher levels of POMC, SSTR5, and MGMT. Conclusions: Microadenomas that strongly express POMC were common among mutated tumors, which may lead to the mechanisms by which very small adenomas secrete excess ACTH to present overt CD. While USP8 mutations were less likely to enhance tumorous ACTH hypersecretion via EGFR-mediated activation, the presence of USP8 mutations may predict favorable responses to the somatostatin analog pasireotide, which exhibits high affinity for SSTR5. In contrast, non-mutated aggressive tumors such as CCA may respond better to the alkylating agent temozolomide because of their significantly weak expression of MGMT.

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“…These alterations could influence functional pathways dictating tumor phenotype, including invasive behavior. A potential relationship between MGMT status and tumor invasion was described in invasive Crooke's cell adenomas, which have decreased expression of MGMT compared with noninvasive ordinary-type adenomas of Cushing's disease (12), and in gastric carcinoma, in which MGMT promoter methylation was associated with lymph node invasion (13). In the context of GBM, Brandes and colleagues (14) recently observed that following treatment, GBM tumors with MGMT promoter methylation recurred at more distal sites from the initial radiation field.…”

Section: Introductionmentioning

confidence: 99%

O(6)-Methylguanine-DNA Methyltransferase Is a Novel Negative Effector of Invasion in Glioblastoma Multiforme

Chahal

Abdulkarim

et al. 2012

Molecular Cancer Therapeutics

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The dismal prognosis of glioblastoma multiforme (GBM) is mostly due to the high propensity of GBM tumor cells to invade. We reported an inverse relationship between GBM angiogenicity and expression of the DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT), which has been extensively characterized for its role in resistance to alkylating agents used in GBM treatment. In the present study, given the major role of angiogenesis and invasion in GBM aggressiveness, we aimed to investigate the relationship between MGMT expression and GBM invasion. Stable overexpression of MGMT in the U87MG cell line significantly decreased invasion, altered expression of invasion-related genes, decreased expression of a 5 b 1 integrin and focal adhesion kinase, and reduced their spindle-shaped morphology and migration compared with the empty vector control. Conversely, short hairpin RNA-mediated stable knockdown of MGMT or its pharmacologic depletion in the MGMT-positive T98G cell line were required for increased invasion. The inverse relationship between MGMT and invasion was further validated in primary GBM patient-derived cell lines. Using paraffin-embedded tumors from patients with newly diagnosed GBM (n ¼ 59), tumor MGMT promoter hypermethylation (MGMT gene silencing) was significantly associated with increased immunohistochemical expression of the proinvasive matricellular protein secreted protein acidic and rich in cysteine (SPARC; P ¼ 0.039, x 2 test). Taken together, our findings highlight for the first time the role of MGMT as a negative effector of GBM invasion. Future studies are warranted to elucidate the role of SPARC in the molecular mechanisms underlying the inverse relationship between MGMT and GBM invasion and the potential use of MGMT and SPARC as biomarkers of GBM invasion.

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High incidence of low O6-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing's disease

Cited by 64 publications

References 23 publications

Treatment of pituitary neoplasms with temozolomide

Treatment of pituitary neoplasms with temozolomide

The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing's disease

O(6)-Methylguanine-DNA Methyltransferase Is a Novel Negative Effector of Invasion in Glioblastoma Multiforme

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