Molecular Analysis of Pheochromocytoma after Maternal Transmission of SDHD Mutation Elucidates Mechanism of Parent-of-Origin Effect

Yeap, Phey Ming; Tobias, Edward S.; Mavraki, Eleni; Fletcher, Alexander; Bradshaw, Nicola; Freel, E. Marie; Cooke, Alexander; Murday, Victoria; Davidson, H. Rosemarie; Perry, Colin; Lindsay, Robert

doi:10.1210/jc.2011-1244

Cited by 56 publications

(44 citation statements)

References 9 publications

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“…• Step 1: SDHD mutation • Step 2: Loss or mutation of the wild-type allele • Step 3: Loss of a further imprinted (paternally silenced and maternally active) tumour suppressor gene from chr11 (thought to be the H19 gene) 22 In this hypothesis, steps 2 and 3 were thought to be explained solely by the obligate loss of the maternal copy of chromosome 11 (both losses generated by one event: the complete loss of the entire maternal chromosome) and that the three-hit model was therefore caused by only two events. That scenario was concordant with the parent-of-origin effect observed, with the mutation transmitted (step 1) on the paternal allele.…”

Section: Genetics Of Pheo-pgl: Non-syndromic Causesmentioning

confidence: 99%

“…That scenario was concordant with the parent-of-origin effect observed, with the mutation transmitted (step 1) on the paternal allele. However, 3 cases of affected individuals who received their mutations from their mothers have been published 22 . In one of those cases, the tumour analysis explained the phenomenon, because in addition to the maternal mutated allele, there was evidence of loss of the wild-type paternal SDHD and loss of the maternal 11p region (including the 11p15 H19 gene).…”

Section: Genetics Of Pheo-pgl: Non-syndromic Causesmentioning

confidence: 99%

See 1 more Smart Citation

Pheochromocytoma and paraganglioma syndromes: genetics and management update

Lefebvre¹,

Foulkes²

2013

Curr. Oncol.

103

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hypertension, perspiration, or pallor. He was referred to genetics because of a family history of pheochromocytoma (pheo): his maternal cousin's daughter had been diagnosed with an abdominal extra-adrenal paraganglioma (pgl). She and her mother underwent genetic testing and were both found to be positive for a SDHB mutation, c.343C>T, p.Arg115*. Our patient's deceased maternal uncle was presumed to be a carrier, because his wife (the affected woman's maternal grandmother) was tested and did not carry the mutation. The patient was tested and was found to be a carrier of the familial mutation, as were his three unaffected children. Case 2A 49-year-old French Canadian man was diagnosed with bilateral neck pgls. He did not report ataxia, skin problems, or other tumours, and the family history was negative for relevant illnesses. Magnetic resonance imaging showed bilateral masses in the carotid spaces. On the left side, the tumour extended from the post-styloid parapharyngeal space, splaying the carotid arteries anteriorly and the internal jugular vein posteriorly. The mass, which arose from the vagus nerve, measured 72×38×46 mm. On the right side, the tumour, which arose from the carotid body, was located in the right carotid bifurcation. It measured 11×14 mm. Because surgery was not possible, the patient was treated with radiotherapy.The genetic work-up included SDHB and SDHD sequencing, the results of which were normal. A deletion and duplication analysis of SDHB, SDHC, and SDHD by multiplex ligation-dependent probe amplification was also normal. On a research basis, SDHAF2 and SDHC sequencing were then done. We identified a SDHC mutation, c.397C>T, p.Arg133*, which is a probable French Canadian founder mutation 1 . Case 3A 67-year-old woman of Ashkenazi Jewish inheritance had a history of a mass in the neck for about 20 ABSTRACT Pheochromocytomas (pheos) and paragangliomas (pgls) are rare tumours of the autonomic nervous system, originating from paraganglia, which are dispersed neuroendocrine organs characterized by catecholamine and peptide-producing cells derived from the neural crest. Medical textbooks have traditionally suggested that 10% of pheos are heritable. However, the frequency of heritable pheo has been underestimated. Three syndromic conditions-Von Hippel-Lindau (vhl), multiple endocrine neoplasia type 2 (men2), and neurofibromatosis type 1 (nf1)-and three genes-subunits of the succinate dehydrogenase (SDH) complex: SDHB, SDHC, and SDHD-are established causes of hereditary pheo-pgl. In the last few years, four new genes (SDHA, SDHAF2, MAX, and TMEM127) have been found to be associated with predisposition to these tumours. The present review, illustrated by three case reports, gives an update of the genetic basis of pheo-pgl and of the parent-of-origin effect implicated in the transmission of SDHD and SDHAF2. We discuss the referral criteria that should guide the decision to offer genetic testing to affected patients. We also specify the genes that are most likely implicated-based on particular featur...

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Section: Genetics Of Pheo-pgl: Non-syndromic Causesmentioning

confidence: 99%

Section: Genetics Of Pheo-pgl: Non-syndromic Causesmentioning

confidence: 99%

Pheochromocytoma and paraganglioma syndromes: genetics and management update

Lefebvre¹,

Foulkes²

2013

Curr. Oncol.

103

View full text Add to dashboard Cite

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“…Such a combination is not usually sufficient to drive tumorigenesis. In support of this hypothesis is the observation that in one case of paraganglioma after maternal transmission of a SDHD mutation, there was loss of the paternal SDHD allele and loss of the maternal 11p15.5 imprinted region (Yeap et al 2011). …”

Section: Penetrance and Genotype-phenotype Correlationsmentioning

confidence: 92%

“…Apart from a few exceptional cases in which clinical disease has developed after maternal transmission of a SDHD mutation (Yeap et al 2011), the risk of clinical disease after a maternal transmission appears to be extremely remote. Notably, the paraganglioma phenotype in such cases appears mild or atypical (e.g.…”

Section: Penetrance and Genotype-phenotype Correlationsmentioning

confidence: 99%

15 YEARS OF PARAGANGLIOMA: Genetics and mechanism of pheochromocytoma–paraganglioma syndromes characterized by germline SDHB and SDHD mutations

Baysal

Maher

2015

Endocrine-Related Cancer

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Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine neoplasms that derive from small paraganglionic tissues which are located from skull base to the pelvic floor. Genetic predisposition plays an important role in development of PPGLs. Since the discovery of first mutations in the succinate dehydrogenase D (SDHD) gene, which encodes the smallest subunit of mitochondrial complex II (SDH), genetic studies have revealed a major role for mutations in SDH subunit genes, primarily in SDHB and SDHD, in predisposition to both familial and non-familial PPGLs. SDH-mutated PPGLs show robust expression of hypoxia induced genes, and genomic and histone hypermethylation. These effects occur in part through succinate-mediated inhibition of a-ketoglutarate-dependent dioxygenases. However, details of mechanisms by which SDH mutations activate hypoxic pathways and trigger subsequent neoplastic transformation remain poorly understood. Here, we present a brief review of the genetic and mechanistic aspects of SDH-mutated PPGLs.

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“…Thus, a second paternally imprinted tumor suppressor gene located elsewhere on chromosome 11 may play a decisive role in tumorigenesis, at least in PGL1 and PGL2. In the very few instances of maternal transmission of the disease in PGL1 families, not only was the SDHD or SDHAF2 gene affected but also was the 11p15 region (Pigny et al, 2008;Yeap et al, 2011). This putative tumor suppressor gene has yet to be identified.…”

Section: Sdhdmentioning

confidence: 99%