DNA Mismatch Repair Protein (MSH6) Correlated With the Responses of Atypical Pituitary Adenomas and Pituitary Carcinomas to Temozolomide: The National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors

Hirohata, Taizo; Asano, Kenichiro; Ogawa, Yoshikazu; Takano, Shingo; Amano, Kosaku; Isozaki, Osamu; Iwai, Yoshiyasu; Sakata, Kiyohiko; Fukuhara, Noriaki; Nishioka, Hiroshi; Yamada, Shozo; Shimizu, Fujio; Arita, Kazunori; Takano, Koji; Tominaga, Atsushi; Hizuka, Naomi; Ikeda, Hidetoshi; Osamura, R. Yoshiyuki; Tahara, Shigeyuki; Ishii, Yudo; Kawamata, Takakazu; Shimatsu, Akira; Teramoto, Akira; Matsuno, Akira

doi:10.1210/jc.2012-2924

Cited by 111 publications

(92 citation statements)

References 35 publications

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“…One possible explanation of the controversy is the acquisition of temozolomide resistance due to the loss of MSH6 expression during temozolomide treatments (19,20,39). In our subjects, most patients (58 out of 60) were immunopositive for MSH6.…”

Section: Discussionmentioning

confidence: 77%

“…Several studies have argued that an immunohistochemical MGMT expression analysis is not clinically useful in predicting tumor responses to temozolomide therapy (20,37,38). One possible explanation of the controversy is the acquisition of temozolomide resistance due to the loss of MSH6 expression during temozolomide treatments (19,20,39).…”

Section: Discussionmentioning

confidence: 99%

“…The positive expression of dopamine receptor D2 (DRD2), somatostatin receptors (SSTRs), and EGFR have been shown to predict drug susceptibility to dopamine agonists, somatostatin analogs, and TK inhibitors respectively (12,13,17). In contrast, the negative expression of O 6 -methylguanine DNA methyltransferase (MGMT) and the DNA mismatch repair protein MSH6 have been associated with tumor responsiveness (18,19) and resistance to temozolomide (20) respectively. In order to determine the impact of USP8 mutations in CD, we herein evaluated the clinicopathological features of 60 corticotroph adenomas including 15 CCAs using quantitative real-time PCR (qRT-PCR) and/or immunohistochemistry, and evaluated their relationships with the USP8 mutation status.…”

Section: Introductionmentioning

confidence: 99%

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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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138

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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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Self Cite

138

156

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“…In a study of 13 patients with aggressive pituitary tumours (9 carcinomas), intact MSH6 but not low MGMT was found to be a prognostic indicator of good response to TMZ (104). Other MMRs were not studied.…”

Section: -Dna Mismatch Repair (Mmr) Proteinsmentioning

confidence: 99%

“…www.eje-online.org expression have not been shown to be useful predictors of the response to TMZ (12,25,104,107). R 3.4.7 In patients responding to first-line temozolomide, as assessed after 3 cycles, we suggest treatment to be continued for at least 6 months in total, with consideration for longer duration if continued therapeutic benefit is observed (+000).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

Raverot

Burman

McCormack

et al. 2018

European Journal of Endocrinology

477

583

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Background: Pituitary tumours are common and easily treated by surgery or medical treatment in most cases. However, a small subset of pituitary tumours does not respond to standard medical treatment and presents with multiple local recurrences (aggressive pituitary tumours) and in rare occasion with metastases (pituitary carcinoma). The present European Society of Endocrinology (ESE) guideline aims to provide clinical guidance on diagnosis, treatment and follow-up in aggressive pituitary tumours and carcinomas. Methods: We decided upfront, while acknowledging that literature on aggressive pituitary tumours and carcinomas is scarce, to systematically review the literature according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The review focused primarily on first-and second-line treatment in aggressive pituitary tumours and carcinomas. We included 14 single-arm cohort studies (total number of patients = 116) most on temozolomide treatment (n = 11 studies, total number of patients = 106). A positive treatment effect was seen in 47% (95% CI: 36-58%) of temozolomide treated. Data from the recently performed ESE survey on aggressive pituitary tumours and carcinomas (165 patients) were also used as backbone for the guideline. In patients responding to first-line temozolomide, we suggest continuing treatment for at least 6 months in total. Furthermore, the guideline offers recommendations for patients who recurred after temozolomide treatment, for those who did not respond to temozolomide and for patients with systemic metastasis.

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Long‐term remission in an aggressive Crooke cell adenoma of the pituitary , 18 months after discontinuation of treatment with temozolomide

Asimakopoulou

Tzanela

Koletti

et al. 2013

Clinical Case Reports

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DNA Mismatch Repair Protein (MSH6) Correlated With the Responses of Atypical Pituitary Adenomas and Pituitary Carcinomas to Temozolomide: The National Cooperative Study by the Japan Society for Hypothalamic and Pituitary Tumors

Cited by 111 publications

References 35 publications

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

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

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas

Long‐term remission in an aggressive Crooke cell adenoma of the pituitary , 18 months after discontinuation of treatment with temozolomide

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