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Dive into the research topics where Francesca Schiavi is active.

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Featured researches published by Francesca Schiavi.


Nature Genetics | 2011

Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma

Iñaki Comino-Méndez; Francisco Javier Gracia-Aznárez; Francesca Schiavi; Iñigo Landa; Luis J. Leandro-García; Rocío Letón; Emiliano Honrado; Rocío Ramos-Medina; Daniela Caronia; Guillermo Pita; Álvaro Gómez-Graña; Aguirre A. de Cubas; Lucía Inglada-Pérez; Agnieszka Maliszewska; Elisa Taschin; Sara Bobisse; Giuseppe Pica; Paola Loli; Rafael Hernández-Lavado; José A. Díaz; Mercedes Gómez-Morales; Anna González-Neira; Giovanna Roncador; Cristina Rodríguez-Antona; Javier Benitez; Massimo Mannelli; Giuseppe Opocher; Mercedes Robledo; Alberto Cascón

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.


Nature Genetics | 2010

Germline mutations in TMEM127 confer susceptibility to pheochromocytoma

Yuejuan Qin; Li Qin Yao; Elizabeth E. King; Kalyan Buddavarapu; Romina Lenci; E. Sandra Chocron; James D. Lechleiter; Meghan Sass; Neil Aronin; Francesca Schiavi; Francesca Boaretto; Giuseppe Opocher; Rodrigo A. Toledo; Sergio P. A. Toledo; Charles D. Stiles; Ricardo C T Aguiar; Patricia L M Dahia

Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary. However, the molecular basis of the majority of these tumors is unknown. We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene. In a cohort of 103 samples, we detected truncating germline TMEM127 mutations in approximately 30% of familial tumors and about 3% of sporadic-appearing pheochromocytomas without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a classic mechanism of tumor suppressor gene inactivation. Pheochromocytomas with mutations in TMEM127 are transcriptionally related to tumors bearing NF1 mutations and, similarly, show hyperphosphorylation of mammalian target of rapamycin (mTOR) effector proteins. Accordingly, in vitro gain-of-function and loss-of-function analyses indicate that TMEM127 is a negative regulator of mTOR. TMEM127 dynamically associates with the endomembrane system and colocalizes with perinuclear (activated) mTOR, suggesting a subcompartmental-specific effect. Our studies identify TMEM127 as a tumor suppressor gene and validate the power of hereditary tumors to elucidate cancer pathogenesis.


The Journal of Clinical Endocrinology and Metabolism | 2009

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

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

PURPOSE The aim of the study was to define the frequency of hereditary forms and the genotype/phenotype correlations in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. DESIGN We examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1). In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements. RESULTS Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%). CONCLUSIONS 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.


Clinical Cancer Research | 2012

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.

Nelly Burnichon; Alberto Cascón; Francesca Schiavi; NicolePaes Morales; Iñaki Comino-Méndez; Nasséra Abermil; Lucía Inglada-Pérez; Aguirre A. de Cubas; Laurence Amar; Marta Barontini; Sandra Bernaldo De Quiroś; Jérôome Bertherat; Yves Jean Bignon; Marinus J. Blok; Sara Bobisse; Salud Borrego; Maurizio Castellano; Philippe Chanson; María Dolores Chiara; Eleonora P. M. Corssmit; Mara Giacchè; Ronald R. de Krijger; Tonino Ercolino; Xavier Girerd; Encarna B. Gomez-Garcia; Álvaro Gómez-Graña; Isabelle Guilhem; Frederik J. Hes; Emiliano Honrado; Esther Korpershoek

Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest–derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients. Clin Cancer Res; 18(10); 2828–37. ©2012 AACR.


Annals of Surgery | 2009

Surgical Versus Conservative Management for Subclinical Cushing Syndrome in Adrenal Incidentalomas: A Prospective Randomized Study

Antonio Toniato; Isabella Merante-Boschin; Giuseppe Opocher; Maria Rosa Pelizzo; Francesca Schiavi; Enzo Ballotta

Objective:To compare the clinical outcome of patients with subclinical Cushing syndrome (SCS) due to an adrenal incidentaloma (the autonomous hypersecretion of a small amount of cortisol, which is not enough to cause clinically-evident disease) who underwent surgery or were managed conservatively. Summary Background Data:The most appropriate management of SCS patients is controversial, either adrenalectomy or close follow-up being recommended for their treatment. Methods:Over a 15-year period, 45 SCS patients were randomly selected to undergo surgery (n = 23) or conservative management (n = 22). All surgical procedures were laparoscopic adrenalectomies performed by the same surgeon. All patients were followed up (mean, 7.7 years; range, 2–17 years) clinically by 2 experienced endocrinologists 6 and 12 months after surgery and then yearly, or yearly after joining the trial, particularly monitoring diabetes mellitus (DM), arterial hypertension, hyperlipidemia, obesity, and osteoporosis. The study end point was the clinical outcome of SCS patients who underwent adrenalectomy versus those managed conservatively. Results:All 23 patients in the surgical arm had elective surgery. Another 3 patients randomly assigned to conservative management crossed over to the surgical group due to an increasing adrenal mass >3.5 cm. In the surgical group, DM normalized or improved in 62.5% of patients (5 of 8), hypertension in 67% (12 of 18), hyperlipidemia in 37.5% (3 of 8), and obesity in 50% (3 of 6). No changes in bone parameters were seen after surgery in SCS patients with osteoporosis. On the other hand, some worsening of DM, hypertension, and hyperlipidemia was noted in conservatively-managed patients. Conclusions:Based on the results of this study, laparoscopic adrenalectomy performed by skilled surgeons appears more beneficial than conservative management for SCS patients complying with our selection criteria. This trial is registered with Australian Clinical Trials Registry number, ANZCTR12608000567325.


JAMA | 2010

Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas.

Li Yao; Francesca Schiavi; Alberto Cascón; Yuejuan Qin; Lucía Inglada-Pérez; Elizabeth E. King; Rodrigo A. Toledo; Tonino Ercolino; Elena Rapizzi; Christopher J. Ricketts; Luigi Mori; Mara Giacchè; Antonella Mendola; Elisa Taschin; Francesca Boaretto; Paola Loli; Maurizio Iacobone; Gian Paolo Rossi; Bernadette Biondi; José Viana Lima-Junior; Claudio E. Kater; Marie Bex; Miikka Vikkula; Ashley B. Grossman; Stephen B. Gruber; Marta Barontini; Alexandre Persu; Maurizio Castellano; Sergio P. A. Toledo; Eamonn R. Maher

CONTEXT Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. OBJECTIVES To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. DESIGN, SETTING, AND PARTICIPANTS We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. MAIN OUTCOME MEASURES The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. RESULTS We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. CONCLUSIONS Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.


Molecular Endocrinology | 2010

Research Resource: Transcriptional Profiling Reveals Different Pseudohypoxic Signatures in SDHB and VHL-Related Pheochromocytomas

Elena López-Jiménez; Gonzalo Gómez-López; L. Javier Leandro-García; Iván Muñoz; Francesca Schiavi; Cristina Montero-Conde; Aguirre A. de Cubas; Ricardo Ramires; Iñigo Landa; Susanna Leskelä; Agnieszka Maliszewska; Lucía Inglada-Pérez; Leticia de la Vega; Cristina Rodríguez-Antona; Rocío Letón; Carmen Bernal; Jose M. de Campos; Cristina Diez-Tascón; Mario F. Fraga; Cesar Boullosa; David G. Pisano; Giuseppe Opocher; Mercedes Robledo; Alberto Cascón

The six major genes involved in hereditary susceptibility for pheochromocytoma (PCC)/paraganglioma (PGL) (RET, VHL, NF1, SDHB, SDHC, and SDHD) have been recently integrated into the same neuronal apoptotic pathway where mutations in any of these genes lead to cell death. In this model, prolyl hydroxylase 3 (EglN3) abrogation plays a pivotal role, but the molecular mechanisms underlying its inactivation are currently unknown. The aim of the study was to decipher specific alterations associated with the different genetic classes of PCCs/PGLs. With this purpose, 84 genetically characterized tumors were analyzed by means of transcriptional profiling. The analysis revealed a hypoxia-inducible factor (HIF)-related signature common to succinate dehydrogenase (SDH) and von Hippel-Lindau (VHL) tumors, that differentiated them from RET and neurofibromatosis type 1 cases. Both canonical HIF-1α and HIF-2α target genes were overexpressed in the SDH/VHL cluster, suggesting that a global HIF deregulation accounts for this common profile. Nevertheless, when we compared VHL tumors with SDHB cases, which often exhibit a malignant behavior, we found that HIF-1α target genes showed a predominant activation in the VHL PCCs. Expression data from 67 HIF target genes was sufficient to cluster SDHB and VHL tumors into two different groups, demonstrating different pseudo-hypoxic signatures. In addition, VHL-mutated tumors showed an unexpected overexpression of EglN3 mRNA that did not lead to significantly different EglN3 protein levels. These findings pave the way for more specific therapeutic approaches for malignant PCCs/PGLs management based on the patients genetic alteration.


PLOS Genetics | 2009

The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors

Iñigo Landa; Sergio Ruiz-Llorente; Cristina Montero-Conde; Lucía Inglada-Pérez; Francesca Schiavi; Susanna Leskelä; Guillermo Pita; Roger L. Milne; Javier Maravall; Ignacio Ramos; Víctor Andía; Paloma Rodríguez-Poyo; Antonino Jara-Albarrán; Amparo Meoro; Cristina Del Peso; Luis Arribas; Pedro Iglesias; Javier Caballero; Joaquín Serrano; Antonio Picó; Francisco Pomares; Gabriel Giménez; Pedro López-Mondéjar; Roberto Castello; Isabella Merante-Boschin; Maria Rosa Pelizzo; Didac Mauricio; Giuseppe Opocher; Cristina Rodríguez-Antona; Anna González-Neira

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.


The Journal of Clinical Endocrinology and Metabolism | 2014

Krebs Cycle Metabolite Profiling for Identification and Stratification of Pheochromocytomas/ Paragangliomas due to Succinate Dehydrogenase Deficiency

Susan Richter; Mirko Peitzsch; Elena Rapizzi; Jacques W. M. Lenders; Nan Qin; Aguirre A. de Cubas; Francesca Schiavi; Jyotsna U. Rao; Felix Beuschlein; Marcus Quinkler; Henri Timmers; Giuseppe Opocher; Massimo Mannelli; Karel Pacak; Mercedes Robledo; Graeme Eisenhofer

CONTEXT Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations. OBJECTIVE We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations. DESIGN, SETTING, AND PATIENTS PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites. MAIN OUTCOME MEASURE Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations. RESULTS SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases. CONCLUSIONS Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.


Endocrine-related Cancer | 2013

Long term prognosis of patients with pediatric pheochromocytoma

Birke Bausch; Ulrich F. Wellner; Dirk Bausch; Francesca Schiavi; Marta Barontini; Gabriela Sanso; Martin K. Walz; Mariola Pęczkowska; Georges Weryha; Patrizia Dall'Igna; Giovanni Cecchetto; Gianni Bisogno; Lars C. Moeller; Detlef Bockenhauer; Attila Patócs; Károly Rácz; Dmitry Zabolotnyi; Svetlana Yaremchuk; Iveta Dzivite-Krisane; Frederic Castinetti; David Taïeb; Angelica Malinoc; Ernst von Dobschuetz; Jochen Roessler; Kurt Werner Schmid; Giuseppe Opocher; Charis Eng; Hartmut P. H. Neumann

A third of patients with paraganglial tumors, pheochromocytoma, and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127, and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy were performed in patients diagnosed at <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1, and one patient each in RET, SDHA, and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (P=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, P=0.001 and SDHD vs others, P=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, ten at initial diagnosis and another six during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, P<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation, and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.

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Mercedes Robledo

Instituto de Salud Carlos III

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Alberto Cascón

Instituto de Salud Carlos III

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Lucía Inglada-Pérez

Instituto de Salud Carlos III

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