Gain-of-function mutations in DNMT3A in patients with paraganglioma

Remacha, Laura; Currás-Freixes, María; Torres-Ruíz, Raúl; Schiavi, Francesca; Torres‐Pérez, Rafael; Calsina, Bruna; Letón, Rocío; Comino-Méndez, Iñaki; Roldán-Romero, Juan María; Montero‐Conde, Cristina; Santos, María; Pérez, Lucía Inglada; Pita, Guillermo; Alonso, María R.; Honrado, Emiliano; Pedrinaci, Susana; Crespo‐Facorro, Benedicto; Percesepe, Antonio; Falcioni, Maurizio; Rodríguez‐Perales, Sandra; Korpershoek, Esther; Ramón‐Maiques, Santiago; Opocher, Giuseppe; Rodríguez‐Antona, Cristina; Robledo, Mercedes; Cascón, Alberto

doi:10.1038/s41436-018-0003-y

Cited by 81 publications

(51 citation statements)

References 39 publications

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“…The major genetic alterations involve RET (rearranged during transfection) is the causative gene underlying multiple endocrine neoplasia (MEN) type 2A and 2B that are more often associated with pheochromocytomas), VHL that causes von Hippel–Lindau disease, NF1 associated with neurofibromatosis type 1, and the SDHB , SDHD , and SDHC genes encoding subunits B, D, and C of the succinate dehydrogenase enzyme complex involved in the Krebs cycle. More rarely, germline mutations are identified in SDHA (succinate dehydrogenase subunit A), TMEM127 (t ransmembrane protein 127), FH (fumarate hydratase), KIF1Bβ (Kinesin-like protein), MAX (MYC-associated factor X), HIF2A ( hypoxia-inducible factor 2 alpha) or EPAS1 , PHD1 (prolyl hydroxylase) (also known as EGLN2 ), EGLN1 (formerly known as PHD2), SDHAF1, SDHAF2 (the Succinate Dehydrogenase Assembly Factors), BAP1 (BRCA1 associated protein-1), and KMT2D (Histone-lysine N-methyltransferase 2D; also known as MLL2) and DNMT3A (DNA cytosine-5-methyltransferase 3A) [ 68 , 69 , 70 , 71 , 72 , 73 ].…”

Section: Clinical Implications Of the Diagnosis Of Paragangliomamentioning

confidence: 99%

The Diagnosis and Clinical Significance of Paragangliomas in Unusual Locations

Sylvia

Ezzat

Mete

2018

JCM

121

108

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Paragangliomas are neuroendocrine neoplasms, derived from paraganglia of the sympathetic and parasympathetic nervous systems. They are most commonly identified in the head and neck, being most frequent in the carotid body, followed by jugulotympanic paraganglia, vagal nerve and ganglion nodosum, as well as laryngeal paraganglia. Abdominal sites include the well-known urinary bladder tumors that originate in the Organ of Zuckerkandl. However, other unusual sites of origin include peri-adrenal, para-aortic, inter-aortocaval, and paracaval retroperitoneal sites, as well as tumors in organs where they may not be expected in the differential diagnosis of neuroendocrine neoplasms, such as thyroid, parathyroid, pituitary, gut, pancreas, liver, mesentery, lung, heart and mediastinum. The distinction of these lesions from epithelial neuroendocrine neoplasms is critical for several reasons. Firstly, the determination of clinical and biochemical features is different from that used for epithelial neuroendocrine tumors. Secondly, the genetic implications are different, since paragangliomas/pheochromocytomas have the highest rate of germline susceptibility at almost 40%. Finally, the characterization of metastatic disease is unique in these highly syndromic lesions. In this review, we summarize updated concepts by outlining the spectrum of anatomic locations of paragangliomas, the importance of morphology in establishing the correct diagnosis, the clinical implications for management, and the impact of genetics on the distinction between multifocal primary tumors compared with malignant disease.

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Section: Clinical Implications Of the Diagnosis Of Paragangliomamentioning

confidence: 99%

The Diagnosis and Clinical Significance of Paragangliomas in Unusual Locations

Sylvia

Ezzat

Mete

2018

JCM

121

108

View full text Add to dashboard Cite

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“…DNMT3A, SLC25A11, GOT2, IDH3B, KMT2D) [44][45][46][47][48][49] have been identified that lead to the development of P-PGL [50]; many of the germline mutations are readily discovered with the next-generation sequencing method with 98.7 % sensitivity [51,52]. A novel pan-genomic bioinformatic analysis from 2017, of a TCGA (The Cancer Genome Atlas) cohort of 173 patients with P-PGLs have led to distinct molecular clustering containing mutations with similar biology and pathogenesis [48].…”

Section: Sdha Sdhb Sdhc Sdhd Sdhaf2 Vhl Egln1/2 Fh Mdh2 Idhmentioning

confidence: 99%

Precision Surgery for Pheochromocytomas and Paragangliomas

2019

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Since Felix Fränkel’s account of pheochromocytoma in 1886, great discoveries and vast advancements in the diagnosis, genetics, anatomical and functional imaging techniques, and surgical management of pheochromcytoma and paraganglioma (P-PGL) have been made. The improved insight in the pathophysiology of P-PGL and more accurate detection methods enable physicians to tailor the treatment plan to an individual based on the genetic profile and tumor behavior. This review will cover briefly the clinical features, diagnosis, genetic mutations, and imaging modalities that are used to guide current surgical management of these rare and interesting endocrinopathies.

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“…Additionally, hitherto unsolved cases with a clear syndromic form of endocrine neoplasia, or those with a confirmed family history of the disease, may benefit from extended genetic analysis, e.g. whole-exome sequencing, which may reveal a novel genetic cause for the disease, ending the diagnostic odyssey [30].…”

Section: Genetic Testingmentioning

confidence: 99%

Inherited Endocrine Neoplasia— A Comprehensive Review from Gland to Gene

Deng

Izatt

2019

Curr Genet Med Rep

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Purpose of the Review There has been a significant expansion in our knowledge of inherited endocrine neoplasia. This review describes syndromic and non-syndromic hereditary endocrine tumours, associated genetic testing, and progress in the management of the disease. Recent Findings Disease-targeted genetic testing for endocrine neoplasia is routinely available, including recently identified endocrine tumour susceptibility genes GPR101, GCM2, DICER1, and ARMC5. The recommendations for surveillance of those at risk of endocrine neoplasia are still evolving, as the evidence base is limited due to the rarity of these diseases. However, in MEN2, pre-emptive thyroidectomy is established surgical practice and may also be considered for other thyroid neoplastic conditions including DICER1 and PTEN. In advanced MTC, targeted medical therapies are now licensed for use. Summary Identifying patients with endocrine neoplasia formerly relied on clinical, biochemical, and radiological assessment. Increasingly, early genetic diagnosis identifies pre-symptomatic patients, enabling personalised medical care by informing ongoing surveillance and therapeutic interventions to improve outcomes.

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Gain-of-function mutations in DNMT3A in patients with paraganglioma

Abstract: Our findings suggest that DNMT3A may be a susceptibility gene for paragangliomas and, if confirmed in future studies, would represent the first example of gain-of-function mutations affecting a DNA methyltransferase gene involved in cancer predisposition.

Cited by 81 publications

References 39 publications

The Diagnosis and Clinical Significance of Paragangliomas in Unusual Locations

The Diagnosis and Clinical Significance of Paragangliomas in Unusual Locations

Precision Surgery for Pheochromocytomas and Paragangliomas

Inherited Endocrine Neoplasia— A Comprehensive Review from Gland to Gene

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