Oncogenic <i>FGFR1</i> mutation and amplification in common cellular origin in a composite tumor with neuroblastoma and pheochromocytoma

Tasaka, Kachio; Ueno, Hikaru; Yamasaki, Kai; Okuno, Tatsusada; Isobe, Tomoya; Kimura, Shunsuke; Umeda, Katsutsugu; Hara, Junichi; Ogawa, Seishi; Takita, Junko

doi:10.1111/cas.15260

Cited by 5 publications

(3 citation statements)

References 25 publications

(61 reference statements)

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“…We have, in previous studies on neural crest cells during embryogenesis as well as in neuroblastoma, observed that the HIF-2α protein non-canonically localizes to the cytoplasm 28 , 30 . There was a clear distinction between the percentage of tumors positive for cytoplasmic vs. nuclear protein in PPGLs, and considering their proposed shared ancestor cells, the neural crest, with neuroblastoma (shown in e.g., composite tumors 42 ), these findings are of importance to further understand PPGL initiation and subtype distinction.…”

Section: Discussionmentioning

confidence: 93%

Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma

Karakaya,

Gunnesson,

Elias

et al. 2023

Sci Rep

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Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2α correlate to an aggressive tumor phenotype. We show that HIF-2α localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2α was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2α expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients.

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Section: Discussionmentioning

confidence: 93%

Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma

Karakaya,

Gunnesson,

Elias

et al. 2023

Sci Rep

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show abstract

“…We have, in previous studies on neural crest cells during embryogenesis as well as in neuroblastoma, observed that the HIF-2α protein non-canonically localizes to the cytoplasm 27,29 . There was a clear distinction between the percentage of tumors positive for cytoplasmic vs. nuclear protein in PPGLs, and considering their proposed shared ancestor cells, the neural crest, with neuroblastoma (shown in e.g., composite tumors 37 ), these findings are of importance to further understand PPGL initiation and subtype distinction.…”

Section: Discussionmentioning

confidence: 93%

Cytoplasmic HIF-2α correlates to proliferation and predicts worse outcome in sympathetic paraganglioma

Karakaya

Gunnesson

Elias

et al. 2022

Preprint

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Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features and presenting as a useful resource. Mutations in the pseudohypoxic marker EPAS1/HIF-2a correlates to an aggressive tumor phenotype. We show that HIF-2a unexpectedly localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2a was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that cytoplasmic HIF-2a expression serves as a useful clinical marker to differentiate subtypes and predicting outcome, and hence can be used for improved targeted treatment in PPGLs.

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“…Interestingly, most mutations (80%) were shared by all samples in both components, indicating that NB and PCC evolved from the same clone. Also, the presence of mutation and focal amplification of the FGFR1 oncogene in both components suggests that this gene may be a primary driver of this tumor ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Composite pheochromocytoma with ganglioneuroma component: A report of three cases

et al. 2022

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Composite pheochromocytoma (CP) is a very rare tumor originating from neural crest cells, predominantly composed of pheochromocytoma (PCC), a chromaffin cell tumor arising in adrenal medulla, and ganglioneuroma, a tumor derived from autonomic ganglion cells of the nervous system. Moreover, CP may be present in the hereditary syndromes of which pheochromocytoma is part. Literature offers scarce data on this subject, and particularly about its biological behavior, clinical evolution, and molecular profile. We report the phenotype and outcome of three cases of CP (PCC and ganglioneuroma components), followed up at the Endocrine Service of the Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, Brazil. Two nonsyndromic patients (cases 1 and 2) were negative to germline mutations in genes VHL, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and MAX, while the third case (case 3) had clinical diagnosis of neurofibromatosis syndrome. Cases 1, 2, and 3 were diagnosed at 29, 39, and 47 years old, respectively, and were followed up for 3, 17, and 9 years without no CP recurrence. All cases had apparent symptoms of catecholaminergic excess secreted by PCC. Ganglioneuroma, the neurogenic component present in all three cases, had a percentage representation ranging from 5% to 15%. Tumors were unilateral and large, measuring 7.0 cm × 6.0 cm × 6.0 cm, 6.0 cm × 4.0 cm × 3.2 cm, and 7.5 cm × 6.0 cm × 4.5 cm, respectively. All cases underwent adrenalectomy with no recurrence, metastasis, or development of contralateral tumor during follow-up. Genetic testing has been scarcely offered to CP cases. However, a similar frequency of genetic background is found when compared with classic PCC, mainly by the overrepresentation of NF1 cases in the CP subset. By literature review, we identified a notorious increase in cases reported with CP in the last decade, especially in the last 3 years, indicating a recent improvement in the diagnosis of this rare disorder in clinical practice.

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Oncogenic FGFR1 mutation and amplification in common cellular origin in a composite tumor with neuroblastoma and pheochromocytoma

Cited by 5 publications

References 25 publications

Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma

Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma

Cytoplasmic HIF-2α correlates to proliferation and predicts worse outcome in sympathetic paraganglioma

Case Report: Composite pheochromocytoma with ganglioneuroma component: A report of three cases

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