MAPK activation and<i>HRAS</i>mutation identified in pituitary spindle cell oncocytoma

Miller, Michael B.; Bi, Wenya Linda; Ramkissoon, Lori; Kang, Yun Jee; Abedalthagafi, Malak; Knoff, David; Agarwalla, Pankaj K.; Wen, Patrick Y.; Reardon, David A.; Alexander, Brian M.; Laws, Edward R.; Dunn, Ian F.; Beroukhim, Rameen; Ligon, Keith L.; Ramkissoon, Shakti

doi:10.18632/oncotarget.9244

Cited by 28 publications

(30 citation statements)

References 55 publications

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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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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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“…However, this is still controversial. Recently, Miller et al [ 9 ] found a low mutation-rate and copy neutral profiles of ASCO, consistent with this tumor's low-grade nature. From 1 patient, they revealed a MEN1 frameshift-mutation (p.L117fs) and a cooccurring somatic H-RAS (p.Q61R) activating point-mutation present in primary and recurrent tumors.…”

Section: Discussionmentioning

confidence: 55%

Malignant adenohypophysis spindle cell oncocytoma with repeating recurrences and a high Ki-67 index

Kong

et al. 2017

Medicine

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Adenohypophysis spindle cell oncocytoma (ASCO) is a rare tumor recently reported by Roncaroli et al in 2002. This tumor is considered a grade I tumor by the World Health Organization.We report a rare case of malignant ASCO with repeating recurrences and a high Ki-67 index—a challenging diagnosis guided by clinical presentations, radiological signs, and postoperative pathological tests.We represent a 30-year-old man who had suffered from headaches, diplopia, and impaired visual field and acuity. His magnetic resonance imaging revealed an abnormal sellar mass and was originally misdiagnosed as a pituitary macroadenoma. We present detailed analysis of the patient's disease course and review relevant literature.When surgically treated, the specimen revealed a typical histopathology pattern of ASCO. The tumor recurred for several times and the patient underwent 3 surgeries and 1 γ-knife treatment, which was accompanied by a continuously increasing Ki-67 index.This is the first reported case of malignant ASCO (WHO III–IV grade). Despite its rarity, ASCO should be considered in the differential diagnosis of sellar lesions that mimic pituitary adenomas.

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“…SCO is a rare entity, described first in 2002 with few subsequent case reports to date . As described first by Roncaroli et al , SCO occurs most commonly in middle and older age groups with mean age of 61.6 years .…”

Section: Discussionmentioning

confidence: 84%

“…34 Miller et al have shown MAPK activity in a series of four cases of SCO. 27 Alexandrescu demonstrated expression of p-Akt, p-mTOR, and Gli2 in a single case of SCO. 35 The MAPK pathway, Akt/m-TOR pathway and Gli2 can be future potential therapeutic targets.…”

Section: Discussionmentioning

confidence: 97%

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Spindle cell oncocytoma of adenohypophysis: Review of literature and report of another recurrent case

et al. 2017

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Spindle cell oncocytoma (SCO) of adenohypophysis was first described in 2002 by Roncaroli et al. as a new entity in the tumors originating from adenohypophysis. It was subsequently recognized as a distinct entity in the 2007 WHO classification of CNS tumors and retained in the current updated classification. In contrast to that suggested by the original authors, this tumor does have a potential for recurrence as first described by Kloub et al. and later with many such case reports. This tumor can be confused with other sellar tumors like pituicytomas and pituitary adenoma, both radiologically and histopathologically. However, it is imperative to differentiate these tumors from the above-mentioned differential diagnoses as it certainly has a recurrent potential. To date only 34 cases of SCO have been published in the English literature. Herein we present a rare SCO case with unusually aggressive course in a 64-year-old man, which recurred 4 years after the initial diagnosis.

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MAPK activation andHRASmutation identified in pituitary spindle cell oncocytoma

Cited by 28 publications

References 55 publications

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

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

Malignant adenohypophysis spindle cell oncocytoma with repeating recurrences and a high Ki-67 index

Spindle cell oncocytoma of adenohypophysis: Review of literature and report of another recurrent case

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