Clinically Guided Genetic Screening in a Large Cohort of Italian Patients with Pheochromocytomas and/or Functional or Nonfunctional Paragangliomas

Mannelli, Massimo; Castellano, Maurizio; Schiavi, Francesca; Filetti, Sébastiano; Giacchè, Mara; Mori, Luigi; Pignataro, Viviana; Bernini, Gianpaolo; Giaché, Valentino; Bacca, Alessandra; Biondi, Bernadette; Corona, Giovanni; Trapani, Giuseppe Di; Grossrubatscher, Erika; Reimondo, Giuseppe; Arnaldi, Giorgio; Giacchetti, Gilberta; Veglio, Franco; Loli, Paola; Colao, Annamaria; Ambrosio, Maria Rosaria; Terzolo, Massimo; Letizia, Claudio; Ercolino, Tonino; Opocher, Giuseppe

doi:10.1210/jc.2008-2419

Cited by 274 publications

(326 citation statements)

References 33 publications

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“…Genetic testing algorithms based on clinical features (that is, tumour localization, malignancy and syndromic characteristics), biochemical profile (that is, types of catecholamines secreted by the tumour) or immunohistochemistry pattern have been developed to aid prioritizing genetic testing of a single or a few PPGLs susceptibility genes [5][6][7][8][9] . Although this approach is helpful for patients in whom a pathogenic driver mutation is identified promptly, it can be cumbersome when this quick identification does not happen, as the analysis must be extended to the remaining susceptibility genes.…”

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Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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Phaeochromocytomas and paragangliomas (PPGLs) are neural-crest-derived tumours of the sympathetic or parasympathetic nervous system that are often inherited and are genetically heterogeneous. Genetic testing is recommended for patients with these tumours and for family members of patients with hereditary forms of PPGLs. Due to the large number of susceptibility genes implicated in the diagnosis of inherited PPGLs, next-generation sequencing (NGS) technology is ideally suited for carrying out genetic screening of these individuals. This Consensus Statement, formulated by a study group comprised of experts in the field, proposes specific recommendations for the use of diagnostic NGS in hereditary PPGLs. In brief, the study group recommends target gene panels for screening of germ line DNA, technical adaptations to address different modes of disease transmission, orthogonal validation of NGS findings, standardized classification of variant pathogenicity and uniform reporting of the findings. The use of supplementary assays, to aid in the interpretation of the results, and sequencing of tumour DNA, for identification of somatic mutations, is encouraged. In addition, the study group launches an initiative to develop a gene-centric curated database of PPGL variants, with annual re-evaluation of variants of unknown significance by an expert group for purposes of reclassification and clinical guidance.

Funding Agencies|Cancer Prevention and Research Institute of Texas (CPRIT) [RP101202, RP57154]; Department of Defense [CDMRP W81XWH-12-1-0508]; Voelcker Fund; National Institutes of Health (NIH)s National Center for Research Resources; National Center for Advancing Translational Sciences [8UL1TR000149]; INSERM; French National Cancer Institute (INCA); Direction Generale de lOffre de Soins (DGOS); INCA [INCA-DGOS_8663]; European Union [633983]; Brazilian National Council for Scientific and Technological Development (CNPq); Cancer Research for PErsonalized Medicine (CARPEM); ERC Advanced Researcher Award

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Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

et al. 2016

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“…13,15 The SDH complex is comprised of or modified by proteins encoded by SDHA, SDHB, SDHC, SDHD, and SDHAF2. 16 Germline mutations in these genes have been identified in patients with paraganglioma, [17][18][19][20][21][22] renal cell carcinoma, 23,24 and GIST, 11,12 as well as syndromes of multiple tumor types. 11,13 In GIST, alterations in SDH have most commonly been reported in SDHB, but also have been found in SDHC, SDHD, and, recently, SDHA.…”

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Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

et al. 2013

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Gastrointestinal stromal tumors (GISTs) are usually driven by mutations in KIT or PDGFRA, although 15% of GISTs in adults and 490% in children lack such mutations. The majority of gastric KIT/PDGFRA wild-type GISTs show distinctive morphological and clinical features and loss of expression of succinate dehydrogenase (SDH) B. Only a small subset of SDHB-deficient GISTs carries loss-of-function mutations in SDHB, SDHC, or SDHD. Because of the complexity of its locus (15 exons) and the presence of three pseudogenes, SDHA is rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of expression of SDHA in a small group of paragangliomas. We sought to determine whether immunohistochemistry for SDHA could identify GISTs with SDHA mutations. Tumors (n ¼ 33) with pathological features of SDH-deficient GIST were analyzed for expression of SDHA and SDHB by immunohistochemistry, and SDHA exons were sequenced from tumors lacking SDHA expression. Exons harboring somatic mutations were examined in DNA from corresponding normal tissue. All 33 tumors showed loss of SDHB expression. A total of 9 out of 33 (27%) tumors also lacked expression of SDHA. SDHA-deficient GISTs affected five men and four women (median age 38 years). SDHA expression was intact in the 24 remaining tumors, including those with known SDHB (n ¼ 3) or SDHC (n ¼ 2) mutations. Nonsense (n ¼ 8) or missense (n ¼ 1) mutations in SDHA were identified in all SDHA-deficient tumors. Heterozygous mutations were also found in DNA from normal tissues from six patients with available material. Somatic loss of the second allele has been found in seven tumors, five by loss of heterozygosity, one by a 13-bp deletion, and one by a missense mutation. Loss of SDHA expression in GIST reliably predicts the presence of SDHA mutations, which represent a relatively common cause of SDH-deficient GIST in adults. Immunohistochemistry for SDHA can be used to select patients for SDHA-specific genetic testing.

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“…7,8 Pheochromocytomas are unique among other tumors, because 25-30% of them arise due to germ-line mutations related to hereditary endocrine tumor syndromes. 6,9 Four major syndromes are known to be associated with pheochromocytomas: (1) multiple endocrine neoplasia type 2, (2) neurofibromatosis type 1, (3) von Hippel-Lindau disease and (4) hereditary paraganglioma syndromes. Mutations of the RET (rearranged during transfection), NF1, VHL and SDH (succinate dehydrogenase) B, C and D genes, respectively, are responsible for these syndromes.…”

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MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

et al. 2010

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MicroRNAs are involved in the pathogenesis of several tumors, however, there have been no data on microRNA expression in pheochromocytomas to date. The objective of our study was to perform microRNA expression profiling in sporadic and hereditary benign, and recurring adrenomedullary tumors. Furthermore, the applicability of formalin-fixed paraffin-embedded tissue samples for the analysis of microRNA expression in pheochromocytomas was examined. MicroRNA expression data of three matched frozen and formalin-fixed paraffin-embedded samples were correlated. A total of 21 formalin-fixed paraffin-embedded samples (sporadic benign, multiple endocrine neoplasia 2, von Hippel-Lindau disease, sporadic recurring) were subjected to microRNA expression profiling using microarrays. MicroRNAs with significant differences in expression were validated and sample sizes were extended including tumors from neurofibromatosis type 1 patients by real-time quantitative reverse-transcription PCR (n ¼ 33). MicroRNA target prediction was carried out by TargetScan and MicroCosm Targets. Pathway analysis of targets was performed by Ingenuity Pathway Analysis and DIANA mirPath. Furthermore, microRNA expression profiles of a malignant pheochromocytoma and a pair of primary and recurrent tumors were studied by TaqMan Human MicroRNA Cards. MicroRNA expression correlated well between frozen and formalin-fixed paraffinembedded samples (70-92%). Microarray analysis revealed 16 significantly differentially expressed microRNAs. Five of these were validated by real-time RT-PCR. miR-139-3p, miR-541 and miR-765 were significantly differentially expressed between sporadic benign and von Hippel-Lindau-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in multiple endocrine neoplasia type 2 and sporadic recurring pheochromocytomas, respectively. Pathway analysis revealed the possible involvement of Notch-and G-proteincoupled receptor signaling in tumor recurrence. MicroRNA expression profiles in the primary recurrent and recurring malignant comparisons have been similar. In conclusion, we have proved that formalin-fixed paraffinembedded samples can be used for the analysis of microRNA expression in pheochromocytomas. MicroRNA expression patterns differ between various sporadic, hereditary and recurring tumors and miR-1225-3p may be useful for identifying recurring pheochromocytomas.

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Clinically Guided Genetic Screening in a Large Cohort of Italian Patients with Pheochromocytomas and/or Functional or Nonfunctional Paragangliomas

Abstract: The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate clinical evaluation of patients are strong indicators of which genes should be screened first.

Cited by 274 publications

References 33 publications

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

MicroRNA expression profiling in benign (sporadic and hereditary) and recurring adrenal pheochromocytomas

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