<i>EPAS1</i> Mutations and Paragangliomas in Cyanotic Congenital Heart Disease

Vaidya, Anand; Flores, Shahida K.; Cheng, Zi Ming; Nicolas, Marlo; Deng, Yilun; Opotowsky, Alexander R.; Lourenço, Delmar Munir; Barletta, Justine A.; Rana, Huma Q.; Pereira, Maria Adelaide Albergaria; Toledo, Rodrigo A.; Dahia, Patricia L.M.

doi:10.1056/nejmc1716652

Cited by 47 publications

(38 citation statements)

References 5 publications

(8 reference statements)

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“…smoking) should be avoided in individuals with SDH genes or MAX mutations (2). This recommendation was reinforced by recent data showing a gain-offunction somatic mutation of EPAS1 -which encodes a transcription factor involved in the physiological response to oxygen concentration changes -in PGL/PCCs of four of five evaluated patients (80%) diagnosed with chronic hypoxemia due to cyanotic congenital cardiopathy (42).…”

Section: Discussionmentioning

confidence: 95%

Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

Gaviria¹,

Soares²,

Costa³

et al. 2019

Archives of Endocrinology and Metabolism

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Objective: Paraganglioma (PGL) and pheochromocytoma (PCC) are rare neuroendocrine tumors that were considered to be predominantly sporadic. However, with the identification of novel susceptibility genes over the last decade, it is currently estimated that up to 40% of cases can occur in the context of a hereditary syndrome. We aimed to characterize PGL/PCC families to exemplify the different scenarios in which hereditary syndromes can be suspected and to emphasize the importance for patients and their families of making an opportune genetic diagnosis. Materials and methods: Retrospective analysis of patients diagnosed with PGL/PCC. Germline mutations were studied using next-generation sequencing panels including SDHA, SDHB, SDHC and SDHD. Clinical data were collected from clinical records, and all patients received genetic counseling. Results: We describe 4 families with PGL/ PCC and germline mutations in SDH complex genes. 2 families have SDHB mutations and 2 SDHD mutations. The clinical presentation of the patients and their families was heterogeneous, with some being atypical according to the literature. Conclusions: PGL/PCC are more commonly associated with a germline mutation than any other cancer type, therefore, all individuals with these types of tumors should undergo genetic risk evaluation. NGS multigene panel testing is a cost-effective approach given the overlapping phenotypes. Individuals with germline mutations associated with PGL/PCC should undergo lifelong clinical, biochemical and imaging surveillance and their families should undergo genetic counseling. For all these reasons, it is critical that all medical staff can suspect and diagnose these inherited cancer predisposition syndromes.

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Section: Discussionmentioning

confidence: 95%

Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

Gaviria¹,

Soares²,

Costa³

et al. 2019

Archives of Endocrinology and Metabolism

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“…A higher reported incidence of hypertrophic pyloric stenosis in esophageal atresia patients (40) supports this hypothesis. Moreover, reports on the association between congenital malformations and increased cancer risk suggest a shared etiology (41–45).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide meta-analysis identifiesBARX1andEML4-MTA3as new loci associated with infantile hypertrophic pyloric stenosis

Fadista

Skotte

Geller

et al. 2018

Human Molecular Genetics

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Infantile hypertrophic pyloric stenosis (IHPS) is a disorder of young infants with a population incidence of ∼2/1000 live births, caused by hypertrophy of the pyloric sphincter smooth muscle. Reported genetic loci associated with IHPS explain only a minor proportion of IHPS risk. To identify new risk loci, we carried out a genome-wide meta-analysis on 1395 surgery-confirmed cases and 4438 controls, with replication in a set of 2427 cases and 2524 controls. We identified and replicated six independent genomic loci associated with IHPS risk at genome wide significance (P < 5 × 10−8), including novel associations with two single nucleotide polymorphisms (SNPs). One of these SNPs, rs6736913 [odds ratio (OR) = 2.32; P = 3.0 × 10−15], is a low frequency missense variant in EML4 at 2p21. The second SNP, rs1933683 (OR = 1.34; P = 3.1 × 10−9) is 1 kb downstream of BARX1 at 9q22.32, an essential gene for stomach formation in embryogenesis. Using the genome-wide complex trait analysis method, we estimated the IHPS SNP heritability to be 30%, and using the linkage disequilibrium score regression method, we found support for a previously reported genetic correlation of IHPS with lipid metabolism. By combining the largest collection of IHPS cases to date (3822 cases), with results generalized across populations of different ancestry, we elucidate novel mechanistic avenues of IHPS disease architecture.

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“…The possibility of multiple additional clinical presentations and novel mutations will further boost our ability to more deeply understand and affect the pathogenesis of this fascinating condition. One example would be a recent report of PPGL associated with cardiac dysplasia 16 . There are still plenty of questions waiting to be answered in relation to the particular mechanisms of tumorigenesis and possible interventions early in the course of the disease to prevent possible adverse outcomes.…”

Section: Disease-modifying Gene Groupmentioning

confidence: 99%

New insights on the pathogenesis of paraganglioma and pheochromocytoma

Kantorovich

Pacák

2018

F1000Res

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Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare chromaffin cell tumors (PPGLs) that at times raise significant challenges in clinical recognition, diagnosis, and therapy and when undiagnosed could associate with severe morbidity. Recent discoveries in PPGL genetics propelled our understanding in the pathophysiology of tumorigenesis and allowed the application of functional classification of pathogenetically distinct groups of PPGLs. This also resulted in a qualitative change in our approach to clinical assessment, diagnosis, and therapy of different subgroups of PPGLs. Establishment of the fact that mutations in multiple components of the PHD–VHL–HIF-2α pathway associate with pseudohypoxia-driven tumorigenesis allowed us not only to better understand the effect of this phenomenon but also to more deeply appreciate the value of functional abnormalities in the physiologic tissue oxygen-sensing mechanism. Mutations in the tricarboxylic acid cycle–related genes opened an additional window into understanding the physiology of one of the basic cellular metabolic pathways and consequences of its disruption. Mutations in the kinase signaling–related genes allow the PPGL field to join a massive innovative process in therapeutic advances in current oncology. New pathophysiologically distinct groups of mutations will widen and deepen our understanding of additional pathways in PPGL tumorigenesis and hopefully introduce additional diagnostic and therapeutic approaches. All of these developments are tremendously important in our understanding of both the normal physiology and pathophysiology of PPGLs and are strong tools and stimuli in the development of modern approaches to all components of medical management.

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EPAS1 Mutations and Paragangliomas in Cyanotic Congenital Heart Disease

Cited by 47 publications

References 5 publications

Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

Pheochromocytoma and paraganglioma: implications of germline mutation investigation for treatment, screening, and surveillance

Genome-wide meta-analysis identifiesBARX1andEML4-MTA3as new loci associated with infantile hypertrophic pyloric stenosis

New insights on the pathogenesis of paraganglioma and pheochromocytoma

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