High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: Implications for genetic testing
ABSTRACT Adrenal and extraadrenal paragangliomas are tumors of chromaffin cells that are usually benign but that may also develop into malignant disease. Mutations of the gene for succinate dehydrogenase subunit B (SDHB) are associated with a high risk of malignancy, but establishing the precise contribution requires relatively large numbers of patients with well-defined malignancy.
We assessed the prevalence of SDHB mutations in a series of patients with malignant paraganglioma.
SDHB mutation testing was carried out in 44 consecutive patients with malignant paraganglioma. Clinical characteristics of patients with malignant disease due to SDHB mutations were compared with those without mutations.
Pathogenic SDHB mutations were found in 13 of the 44 patients (30%). Close to one third of patients had metastases originating from an adrenal primary tumor, compared with a little over two thirds from an extraadrenal tumor. Among the latter patients, the frequency of SDHB mutations was 48%.
This study establishes that missense, nonsense, frameshift, and splice site mutations of the SDHB gene are associated with about half of all malignancies originating from extraadrenal paragangliomas. The high frequency of SDHB germline mutations among patients with malignant disease, particularly when originating from an extraadrenal paraganglioma, may justify a high priority for SDHB germline mutation testing in these patients.
- SourceAvailable from: Tsuyoshi Saito[Show abstract] [Hide abstract]
ABSTRACT: A 70-year-old Japanese woman was referred to our hospital due to hyperhidrosis and rapid weight loss of 10 kg in a month. A lump measuring 26 mm in diameter was detected in the left adrenal gland by computed tomography. Biochemical tests showed high levels of serum and urinary norepinephrine and epinephrine. However, a 123 I-MIBG scintigram failed to detect any accumulation in the left adrenal tumor. A left adrenalectomy was per-formed post clinical diagnosis of 123 I-MIBG negative pheochromocytoma. Microscopically, the tumor exhibited pheo-chromocytoma compatible features. Immunohistochemical analysis revealed low expression of VMAT1 in the tumor compared to the normal, surrounding tissue. To test for a possible genetic alteration of the monoamine transporter genes, we performed whole-exome sequencing of the VMAT1, VMAT2, and NET genes in the tumor. No significant base sequence substitution or deletion/insertion was found in any transporter. This suggests that MIBG negativ-ity is caused by a change that is independent of the base sequence abnormalities, such as an epigenetic change. Furthermore, a retrospective literature review of 123 I-MIBG negative-scintigraphy cases indicates that a negative finding in the 123 I-MIBG scintigram is frequently associated with metastatic pheochromocytomas or SDHB muta-tions. However, a SDHB/D gene mutation has not been identified in the reported case. Although the patient needs careful monitoring following the surgery, to date she has been disease free for 12 months. This study could not find clear reasons for negative conversion, however, investigations of the negative conversion mechanism might reveal significant insights towards the improvement of patient survival.International journal of clinical and experimental pathology 07/2014; 2014(7):4438-4447. · 1.78 Impact Factor
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ABSTRACT: Background:There are no reliable markers of malignancy in phaeochromocytomas (PCC) and paragangliomas (PGL). We investigated the relevance of the mammalian target of rapamycin (mTOR)/AKT and hypoxic pathways as novel immunohistochemical markers of malignancy.Methods:Tissue microarray blocks were constructed with a total of 100 tumours (10 metastatic) and 20 normal adrenomedullary samples. Sections were immunostained for hypoxia-inducible factor 1α (Hif-1α), vascular endothelial growth factor A (VEGF-A), mTOR, carbonic anhydrase IX (CaIX) and AKT. The predictive performance of these markers was studied using univariate, multivariate and receiver operating characteristic analyses.Results:In all, 100 consecutive patients, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Univariate analyses showed Hif-1α overexpression, tumour necrosis, size >5 cm, capsular and vascular invasion to be predictors of metastasis. In multivariate analysis, Hif-1α, necrosis and vascular invasion remained as independent predictors of metastasis. Hif-1α was the most discriminatory biomarker for the presence of metastatic diffusion. Strong membranous CaIX expression was seen in von Hippel-Lindau (VHL) PCC as opposed to other subtypes.Conclusion:Lack of vascular invasion, tumour necrosis and low Hif-1α expression identify tumours with lower risk of malignancy. We propose membranous CaIX expression as a potential marker for VHL disease in patients presenting with PCC.British Journal of Cancer advance online publication, 20 December 2012; doi:10.1038/bjc.2012.538 www.bjcancer.com.British Journal of Cancer 12/2012; 108(2). DOI:10.1038/bjc.2012.538 · 4.82 Impact Factor
Article: SDH mutations in cancer[Show abstract] [Hide abstract]
ABSTRACT: The SDHA, SDHB, SDHC, SDHD genes encode the four subunits of succinate dehydrogenase (SDH; mitochondrial complex II), a mitochondrial enzyme involved in two essential energy-producing metabolic processes of the cell, the Krebs cycle and the electron transport chain. Germline loss-of-function mutations in any of the SDH genes or assembly factor (SDHAF2) cause hereditary paraganglioma/phaeochromocytoma syndrome (HPGL/PCC) through a mechanism which is largely unknown. Owing to the central function of SDH in cellular energy metabolism it is important to understand its role in tumor suppression. Here is reported an overview of genetics, clinical and molecular progress recently performed in understanding the basis of HPGL/PCC tumorigenesis.Biochimica et Biophysica Acta 07/2011; 1807(11):1432-43. DOI:10.1016/j.bbabio.2011.07.003 · 4.66 Impact Factor