The genome-wide mutational landscape of pituitary adenomas

Song, Zhijian; Reitman, Zachary J.; Ma, Zengyi; Chen, Jianhua; Qi-lin, Zhang; Shou, Xuefei; Huang, Chuanxin; Wang, Yongfei; Li, Shiqi; Mao, Ying; Zhou, Lei; Lian, Baofeng; Yan, Hai; Shi, Yongyong; Zhao, Yao

doi:10.1038/cr.2016.114

Cited by 133 publications

(148 citation statements)

References 16 publications

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“…These tumors were more likely to be functional adenomas, without evidence of more aggressive behavior [127,128]. Similar results were further described by other groups in GH-secreting tumors [129,130]. Our group also supported these studies by identifying a subgroup of patients with CD that harbored large genomic aberrations, involving up to 59% of the tumor genome.…”

Section: Copy Number Variations (Cnvs) At the Chromosomal Levelsupporting

confidence: 90%

The Genetics of Pituitary Adenomas

Tatsi

Stratakis

2019

JCM

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The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all patients and may present in the context of relevant family history. Defects in AIP (mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA), MEN1 (coding for menin, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1), PRKAR1A (mutated in Carney complex), GPR101 (involved in X-Linked Acrogigantism or X-LAG), and SDHx (mutated in the so called "3 P association" of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in USP8, GNAS, USP48 and BRAF are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.

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Section: Copy Number Variations (Cnvs) At the Chromosomal Levelsupporting

confidence: 90%

The Genetics of Pituitary Adenomas

Tatsi

Stratakis

2019

JCM

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“…Unfortunately, we failed to detect any nuclear somatic mutations, which have been reported in renal oncocytoma, pituitary spindle cell oncocytoma, and other pituitary adenomas [14,23,24], in our oncocytoma samples. However, frequent mtDNA mutations (averaging 30 mutations per patient) were identified (supplementary material, Table S4).…”

Section: Frequent Mtdna Mutations Lead To Mitochondrial Dysfunctionmentioning

confidence: 55%

Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14‐3‐3η in oncocytomas

Feng

Zhang

et al. 2018

The Journal of Pathology

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Oncocytomas represent a subset of benign pituitary adenomas that are characterized by significant mitochondrial hyperplasia. Mitochondria are key organelles for energy generation and metabolic intermediate production for biosynthesis in tumour cells, so understanding the mechanism underlying mitochondrial biogenesis and its impact on cellular metabolism in oncocytoma is vital. Here, we studied surgically resected pituitary oncocytomas by using multi-omic analyses. Whole-exome sequencing did not reveal any nuclear mutations, but identified several somatic mutations of mitochondrial DNA, and dysfunctional respiratory complex I. Metabolomic analysis suggested that oxidative phosphorylation was reduced within individual mitochondria, and that there was no reciprocal increase in glycolytic activity. Interestingly, we found a reduction in the cellular lactate level and reduced expression of lactate dehydrogenase A (LDHA), which contributed to mitochondrial biogenesis in an in vitro cell model. It is of note that the hypoxia-response signalling pathway was not upregulated in pituitary oncocytomas, thereby failing to enhance glycolysis. Proteomic analysis showed that 14-3-3η was exclusively overexpressed in oncocytomas, and that 14-3-3η was capable of inhibiting glycolysis, leading to mitochondrial biogenesis in the presence of rotenone. In particular, 14-3-3η inhibited LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14-3-3η overexpression and inefficient oxidative phosphorylation in oncocytoma mitochondrial biogenesis. These findings deepen our understanding of the metabolic changes that occur within oncocytomas, and shine a light on the mechanism of mitochondrial biogenesis, providing a novel perspective on metabolic adaptation in tumour cells. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…The most common somatic mutation in acromegaly are the activating mutations of the GNAS gene [76], with a frequency of about 40% (ranging from 10 to 50% depending on the ethnical background) [73, 74, 81–83]. Somatic GNAS mutations are found with equal frequency in both sexes and are more frequent in tumors from older patients [73, 83].…”

Section: Somatic Changes In Somatotropinomasmentioning

confidence: 99%

“…Somatic GNAS mutations are found with equal frequency in both sexes and are more frequent in tumors from older patients [73, 83]. They are also more common in smaller tumors that secrete higher GH levels and are associated with a densely granulated pattern in the histopathology analysis [75, 84].…”

Section: Somatic Changes In Somatotropinomasmentioning

confidence: 99%

The genetic background of acromegaly

Gadelha

Korbonits

2017

Pituitary

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Acromegaly is caused by a somatotropinoma in the vast majority of the cases. These are monoclonal tumors that can occur sporadically or rarely in a familial setting. In the last few years, novel familial syndromes have been described and recent studies explored the landscape of somatic mutations in sporadic somatotropinomas. This short review concentrates on the current knowledge of the genetic basis of both familial and sporadic acromegaly.

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The genome-wide mutational landscape of pituitary adenomas

Cited by 133 publications

References 16 publications

The Genetics of Pituitary Adenomas

The Genetics of Pituitary Adenomas

Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14‐3‐3η in oncocytomas

The genetic background of acromegaly

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