Atypical pituitary adenoma with &lt;i&gt;MEN1&lt;/i&gt; somatic mutation associated with abnormalities of DNA mismatch repair genes; &lt;i&gt;MLH1&lt;/i&gt; germline mutation and &lt;i&gt;MSH6&lt;/i&gt; somatic mutation

Uraki, Shinsuke; Ariyasu, Hiroyuki; Doi, Asako; Furuta, Hiroto; Nishi, Masahiro; Sugano, Kokichi; Inoshita, Naoko; Nakao, Naoyuki; Yamada, Shozo; Akamizu, Takashi

doi:10.1507/endocrj.ej17-0036

Cited by 27 publications

(25 citation statements)

References 39 publications

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“…Germline mutations in the mismatch repair pathway ( MLH1, PMS2, MSH2, MSH6) lead to Lynch syndrome, an autosomal dominant inherited cancer syndrome associated with colorectal, endometrial, ovarian, and other carcinomas. Germline mutations in MLH1 ( 118 ) and MSH2 ( 119 ) have been identified in patients with aggressively growing ACTH-secreting tumors. While somatic variants were found in a single nonfunctioning tumor in 4 mismatch-related genes ( 120 ), microsatellite instability was not found in 107 sporadic pituitary tumor samples ( 121 ).…”

Section: Genetic Mechanisms Of Tumorigenesismentioning

confidence: 99%

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Nadhamuni

Korbonits

2020

Endocrine Reviews

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Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or non-syndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and non-coding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multi-omics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis.

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Section: Genetic Mechanisms Of Tumorigenesismentioning

confidence: 99%

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Nadhamuni

Korbonits

2020

Endocrine Reviews

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“…We used the following antibodies: growth hormone (GH, 54/9 2A2; BioGenex, Fremont, CA, USA), prolactin (polyclonal; DAKO, Santa Clara, CA, USA), beta-thyroid-stimulating hormone (beta-TSH, 0042; DAKO), adrenocorticotropic hormone (ACTH, 02A3; DAKO), beta-follicle-stimulating hormone (beta-FSH, C10; BioGenex), beta-luteinizing hormone (beta-LH, C93; DAKO), Ki-67 (MIB-1,790-4286; Ventana, Tucson, AZ, USA), cytokeratin (CAM5.2; BECTON, Franklin Lakes, NJ, USA), and PD-L1(22C3 pharmDx; DAKO). Immunohistochemistry was performed using the BenchMark Ultra automated system (Ventana, Oro Valley, AZ, USA) as previously described [11]. Several pathologists reviewed specimens and classified pituitary adenomas as suggested in the 2017 WHO classification [21][22][23].…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…Pharmacotherapy for PAs is therefore currently limited, especially for nonfunctioning pituitary adenomas (NFPAs). We recently reported that reduced expression of mismatch repair (MMR) genes MSH6/MSH2 directly promotes pituitary tumor proliferation via the ataxia telangiectasia and Rad3-related-checkpoint kinase 1 (ATR-Chk1) pathway [11,12]. In PAs, MMR genes may be target molecules for future drug therapy.…”

Section: Introductionmentioning

confidence: 99%

MSH6/2 and PD-L1 Expressions Are Associated with Tumor Growth and Invasiveness in Silent Pituitary Adenoma Subtypes

Uraki

Ariyasu

Doi

et al. 2020

IJMS

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Mismatch repair genes mutS homologs 6/2 (MSH6/2) expressions are involved in tumor growth and programmed cell death 1 ligand 1 (PD-L1) expression in tumor immunity, but the direct association with pituitary adenomas (PAs) is not well understood. We aimed to clarify the effects of MSH6/2 and PD-L1 expression on tumor proliferation and invasiveness in nonfunctioning (NF) PAs. We performed immunohistochemistry to classify the NFPAs into gonadotroph adenoma (GAs), silent corticotroph adenomas (SCAs), null cell adenoma (NCAs), and pituitary transcription factor 1 (PIT1) lineage PAs. We evaluated MSH6/2 and PD-L1 mRNA expressions in NFPAs by real-time PCR (n = 73), and statistically analyzed the expressions and clinicopathological factors. We also investigated the effect of MSH6 knockout on PD-L1 expression in AtT-20ins and GH3. MSH6/2 expressions were significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. MSH6/2 expressions were positively associated with PD-L1 expression. PD-L1 expression was significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. Although MSH6/2 expressions also tended to be lower in PIT1 lineage PAs than in GAs, PIT1 lineage PAs expressed PD-L1 equivalently to GA, which was unlike SCAs and NCAs. MSH6 knockout in AtT-20ins and GH3 significantly decreased PD-L1 expression (75% and 34% reduction, respectively) with cell proliferation promotion. In conclusion, differences in MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1-lineage PAs from those of GAs appear to contribute to their clinically aggressive characteristics, such as more proliferation and invasiveness.

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“…At time of submission, this was to our knowledge the first case that described a pituitary tumour as a manifestation of LS. However, in the same year (2017) another case study reported an invasive corticotroph adenoma in a patient with LS (155). The authors suggested that this patient's germline mutation in MLH1 contributed to tumour development by inducing somatic mutations in MSH6 and MEN1 found in the pituitary tumour.…”

Section: Do Germline Mutations In Mmr Genes Contribute To the Development And Course Of Pituitary Tumours?mentioning

confidence: 99%

Cushing’s disease and aggressive pituitary tumours : Aspects on epidemiology, treatment, and long-term follow-up

Bengtsson

2021

Linköping University Medical Dissertations

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This thesis focuses on clinical and epidemiological aspects of aggressive pituitary tumours/carcinomas and Cushing's disease. Pituitary carcinomas account for only 0.1-0.2% of the tumours originating from the anterior pituitary gland and are defined solely by the event of distant metastases, whereas aggressive pituitary tumours are defined by their clinical behaviour of rapid/progressive growth despite optimal treatment with surgery, radiotherapy and medical agents. The prognosis for individuals with aggressive tumours/carcinomas has been poor with few treatment options. However, case reports indicated better outcomes after treatment with the alkylating agent temozolomide. In study I and III, we investigated 24 patients (16 aggressive tumours and 8 carcinomas) given treatment with temozolomide. We found an initial response rate (tumour regression ≥30%) in 10/21 evaluable patients, with complete regression in two carcinomas. Favourable response was associated with low tumour expression of the DNA repair protein MGMT; in responders median 9% (range 5-20%) vs non-responders median 93% (50-100%). Our results also indicated a longer survival in patients with low MGMT. Out of 11 patients with MGMT >10%, nine died with an estimated median survival of 26 months (95% CI 14-38), whereas only 1/6 patients with lower MGMT died from tumour progression during a follow-up of median 83 months (range 12-161).

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Atypical pituitary adenoma with <i>MEN1</i> somatic mutation associated with abnormalities of DNA mismatch repair genes; <i>MLH1</i> germline mutation and <i>MSH6</i> somatic mutation

Cited by 27 publications

References 39 publications

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

Novel Insights into Pituitary Tumorigenesis: Genetic and Epigenetic Mechanisms

MSH6/2 and PD-L1 Expressions Are Associated with Tumor Growth and Invasiveness in Silent Pituitary Adenoma Subtypes

Cushing’s disease and aggressive pituitary tumours : Aspects on epidemiology, treatment, and long-term follow-up

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