Patricia L M Dahia

Publications (20)164.45 Total impact

• Article: Minireview: the busy road to pheochromocytomas and paragangliomas has a new member, TMEM127.

  Shoulei Jiang, Patricia L M Dahia
  [show abstract] [hide abstract]
  ABSTRACT: Characterization of the entire spectrum of cancer-associated genetic disruptions is an overarching goal of contemporary and future oncology and can inform on patient diagnosis, treatment, and surveillance. Hereditary endocrine tumors, by having the potential to reveal the cancer's primary molecular defect, have been especially informative in this realm. Within this group, pheochromocytomas and paragangliomas, neural crest-derived, catecholamine-secreting tumors have come to represent true conduits for gene discovery. About one-third of pheochromocytomas and paragangliomas are now known to result from germline mutations in one of at least eight genes that belong to a variety of functional classes. Greater understanding of the molecular signals transduced by these genes and their respective mutants has advanced our understanding of kinase signaling pathways, hypoxia regulation, and the link between metabolic disruptions and cell growth. A new susceptibility gene without homology to other functional classes has been recently identified and encodes for a three-spanner transmembrane protein, transmembrane protein 127 (TMEM127). Initial insights from in vitro and patient data suggest that this candidate tumor suppressor is linked to the endosomal system and the mechanistic target of rapamycin [formerly mammalian target of rapamycin (mTOR)] pathway, and that mutation carriers often have clinical features that are typically associated with sporadic forms of pheochromocytoma. Functional characterization of transmembrane protein 127 (TMEM127) and discovery of additional pheochromocytoma/paraganglioma susceptibility genes is likely to shed light on our understanding of these tumors and extend these insights to other cancers.
  Endocrinology 03/2011; 152(6):2133-40. · 4.46 Impact Factor
• Article: Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations.

  Katherine A Janeway, Su Young Kim, Maya Lodish, Vânia Nosé, Pierre Rustin, José Gaal, Patricia L M Dahia, Bernadette Liegl, Evan R Ball, Margarita Raygada, [......], Lorna Kelly, Jason L Hornick, Maureen O'Sullivan, Ronald R de Krijger, Winand N M Dinjens, George D Demetri, Cristina R Antonescu, Jonathan A Fletcher, Lee Helman, Constantine A Stratakis
  [show abstract] [hide abstract]
  ABSTRACT: Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1-associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.
  Proceedings of the National Academy of Sciences 01/2011; 108(1):314-8. · 9.68 Impact Factor
• Article: Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas.

  Li Yao, Francesca Schiavi, Alberto Cascon, Yuejuan Qin, Lucia Inglada-Pérez, Elizabeth E King, Rodrigo A Toledo, Tonino Ercolino, Elena Rapizzi, Christopher J Ricketts, [......], Stephen B Gruber, Marta Barontini, Alexandre Persu, Maurizio Castellano, Sergio P A Toledo, Eamonn R Maher, Massimo Mannelli, Giuseppe Opocher, Mercedes Robledo, Patricia L M Dahia
  [show abstract] [hide abstract]
  ABSTRACT: 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. To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. 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. 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. 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. 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.
  JAMA The Journal of the American Medical Association 12/2010; 304(23):2611-9. · 30.03 Impact Factor
• Article: VHL disease.

  Marta Barontini, Patricia L M Dahia
  [show abstract] [hide abstract]
  ABSTRACT: von Hippel-Lindau disease (VHL) disease increases susceptibility to several malignancies, including renal cell carcinoma, haemangioblastomas of the central nervous system or retina and phaeochromocytomas. The VHL tumour suppressor gene, responsible for the disease, encodes for a major regulator of the hypoxic response by targeting the transcription factor hypoxia inducible factor (HIF) for degradation. In this review, we present a synopsis of clinical features of the disease and emphasise unique aspects of VHL syndrome in the paediatric population. Genotype-phenotype associations based on the risk of phaeochromocytoma have pointed to the existence of additional, HIF-independent functions of VHL that remain underexplored. We also examine the progress on these pleiotropic roles of VHL, which contribute to explain clinical features of VHL disease. These advances have important translational implications and are likely to offer a new host of therapeutic options to individuals affected by the disease in the future.
  Best practice & research. Clinical endocrinology & metabolism 06/2010; 24(3):401-13. · 3.89 Impact Factor
• Article: Mutations of the metabolic genes IDH1, IDH2, and SDHAF2 are not major determinants of the pseudohypoxic phenotype of sporadic pheochromocytomas and paragangliomas.

  Li Yao, Marta Barontini, Bruno Niederle, Marion Jech, Roswitha Pfragner, Patricia L M Dahia
  [show abstract] [hide abstract]
  ABSTRACT: Context: Pheochromocytomas and paragangliomas are genetically heterogeneous tumors of neural crest origin. Approximately half of these tumors activate a pseudohypoxic transcription response, which is due in a minority of the cases to germline mutations of the VHL gene or the genes encoding subunits of the metabolic enzyme succinate dehydrogenase (SDH), SDHB, SDHC, or SDHD. However, the genetic basis of the hypoxic-like profile of the remaining tumors is undetermined. Mutations in genes involved in the energy metabolism, isocitrate dehydrogenase 1 (IDH1) and -2 (IDH2) and SDHAF2, a component of SDH, can mimic a pseudohypoxic state. Design: We examined the sequence spanning the mutation-susceptible codons 132 of IDH1 and 172 of IDH2, and the entire coding region of SDHAF2, in 104 pheochromocytomas and paragangliomas, including tumors with a pseudohypoxic expression profile. Results: We did not find mutations in IDH1, IDH2, or SDHAF2 in any of the tumors in this cohort. Conclusion: Conserved residues of IDH1 and IDH2 or the SDHAF2 gene are not frequently mutated in pheochromocytomas and paragangliomas. The molecular basis for activation of a hypoxic response in the majority of tumors without VHL or SDH mutations remains to be defined.
  The Journal of clinical endocrinology and metabolism 03/2010; 95(3):1469-72. · 6.50 Impact Factor
• Article: High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene.

  Rodrigo A Toledo, Simona M Wagner, Flavia L Coutinho, Delmar M Lourenço, Juliana A Azevedo, Viviane C Longuini, Mariana T A Reis, Sheila A C Siqueira, Antonio M Lucon, Marcos R Tavares, Maria C B V Fragoso, Adelaide A Pereira, Patricia L M Dahia, Lois M Mulligan, Sergio P A Toledo
  [show abstract] [hide abstract]
  ABSTRACT: Context: Previous studies have shown that double RET mutations may be associated with unusual multiple endocrine neoplasia type 2 (MEN 2) phenotypes. Objective: Our objective was to report the clinical features of patients harboring a previously unreported double mutation of the RET gene and to characterize this mutation in vitro. Patients: Sixteen patients from four unrelated families and harboring the C634Y/Y791F double RET germline mutation were included in the study. Results: Large pheochromocytomas measuring 6.0-14 cm and weighing up to 640 g were identified in the four index cases. Three of the four tumors were bilateral. High penetrance of pheochromocytoma was also seen in the C634Y/Y791F-mutation-positive relatives (seven of nine, 77.7%). Of these, two cases had bilateral tumors, one presented with multifocal tumors, two cases had large tumors (>5 cm), and one case, which was diagnosed with a large (5.5 x 4.5 x 4.0 cm) pheochromocytoma, reported early onset of symptoms of the disease (14 yr old). The overall penetrance of pheochromocytoma was 84.6% (11 of 13). Development of medullary thyroid carcinoma in our patients seemed similar to that observed in patients with codon 634 mutations. Haplotype analysis demonstrated that the mutation did not arise from a common ancestor. In vitro studies showed the double C634Y/Y791F RET receptor was significantly more phosphorylated than either activated wild-type receptor or single C634Y and Y791F RET mutants. Conclusions: Our data suggest that the natural history of the novel C634Y/Y791F double mutation carries a codon 634-like pattern of medullary thyroid carcinoma development, is associated with increased susceptibility to unusually large bilateral pheochromocytomas, and is likely more biologically active than each individual mutation.
  The Journal of clinical endocrinology and metabolism 03/2010; 95(3):1318-27. · 6.50 Impact Factor
• Source

  Available from: pnas.org

  Article: Targeting of SMAD5 links microRNA-155 to the TGF-beta pathway and lymphomagenesis.

  Deepak Rai, Sang-Woo Kim, Morgan R McKeller, Patricia L M Dahia, Ricardo C T Aguiar
  [show abstract] [hide abstract]
  ABSTRACT: The mechanisms by which microRNA dysfunction contributes to the pathogenesis of diffuse large B cell lymphoma (DLBCL) are not well established. The identification of the genes and pathways directly targeted by these small regulatory RNAs is a critical step to advance this field. Using unbiased genome-wide approaches in DLBCL, we discovered that the oncogenic microRNA-155 (miR-155) directly targets the bone morphogenetic protein (BMP)-responsive transcriptional factor SMAD5. Surprisingly, we found that in DLBCL a noncanonical signaling module linking TGF-beta1 signals to SMAD5 is also active. In agreement with these data, miR-155 overexpression rendered DLBCLs resistant to the growth-inhibitory effects of both TGF-beta1 and BMPs, via defective induction of p21 and impaired cell cycle arrest. In confirmatory experiments, RNAi-based SMAD5 knockdown recapitulated in vitro and in vivo the effects miR-155 overexpression. Furthermore, in primary DLBCLs, miR-155 overexpression inhibited SMAD5 expression and disrupted its activity, as defined by individual and global analyses of its transcriptional targets. Together, our data helped explain miR-155 function, highlighted a hitherto unappreciated role of SMAD5 in lymphoma biology, and defined a unique mechanism used by cancer cells to escape TGF-beta's growth-inhibitory effects.
  Proceedings of the National Academy of Sciences 02/2010; 107(7):3111-6. · 9.68 Impact Factor
• Source

  Available from: E. Sandra Chocron

  Article: Germline mutations in TMEM127 confer susceptibility to pheochromocytoma.

  Yuejuan Qin, Li Yao, Elizabeth E King, Kalyan Buddavarapu, Romina E 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 Stiles, Ricardo C T Aguiar, Patricia L M Dahia
  [show abstract] [hide abstract]
  ABSTRACT: 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.
  Nature Genetics 02/2010; 42(3):229-33. · 35.53 Impact Factor
• Chapter: Molecular Biology of Pheochromocytomas and Paragangliomas

  Elizabeth E. King, Patricia L. M. Dahia
  [show abstract] [hide abstract]
  ABSTRACT: Pheochromocytomas and paragangliomas are catecholamine-secreting neural crest-derived tumors that arise from the adrenal medulla or extraadrenal sympathetic paraganglia, respectively. These tumors are genetically heterogeneous and an increasing fraction can be caused by germline mutations in at least six distinct genes, a finding that has challenged old paradigms of pheochromocytoma biology. In this chapter, we discuss the various hereditary mutations that cause pheochromocytoma and paraganglioma, and describe recent molecular and genomic advances that are uncovering pathogenic signals responsible for tumorigenesis. Similarities amongst the various genetic forms of these tumors are being revealed which can be traced back to the developing neural crest. Despite signaling overlaps, well-established as well as emerging genotype–phenotype correlations of the different hereditary forms imply unique features of each gene that carries translational relevance. Current evidence suggests the existence of additional susceptibility genes that might account for genetically undefined pheochromocytomas and paragangliomas. The progress of recent years in understanding disease pathogenesis is expected to improve patient screening and, in the long term, be translated into broader therapeutic options. KeywordsParaganglioma-SDH genes-SDHD gene-SDHB gene-SDHC gene-VHL gene-NF1 gene-Pheochromocytoma-Mutation-Hereditary cancers-Tumor suppressor genes-Oncogenes
  01/2010: pages 297-305;
• Article: Integrity of the CBL gene in mature B-cell malignancies.

  Morgan R McKeller, Ryan S Robetorye, Patricia L M Dahia, Ricardo C T Aguiar
  Blood 11/2009; 114(19):4321-2. · 9.90 Impact Factor
• Article: A germline mutation of the KIF1Bβ gene on 1p36 in a family with neural and nonneural tumors

  I-Tien Yeh, Romina E. Lenci, Yuejuan Qin, Kalyan Buddavarapu, Azra H. Ligon, Emmanuelle Leteurtre, Christine Do Cao, Catherine Cardot-Bauters, Pascal Pigny, Patricia L. M. Dahia
  [show abstract] [hide abstract]
  ABSTRACT: Recently, the KIF1Bβ gene on 1p36, a region commonly deleted in neural crest cancers, was found to be a proapoptotic factor for sympathetic precursors. KIF1Bβ mutations were detected in pheochromocytomas and neuroblastomas, two sympathetic lineage tumors, suggesting a role for this gene in cancer. Here, we studied five individuals from a three-generation cancer-prone family with a KIF1Bβ germline variant and seven of their tumors, both of neural crest and nonneural origin. Genetic studies including sequencing, copy number analysis and fluorescence in situ-hybridization (FISH) showed retention of both KIF1Bβ alleles in all neural crest-derived tumors in this family, consistent with haploinsufficiency or methylation of the wild-type allele. In contrast, the lung adenocarcinoma from one mutation carrier had somatic loss of the wild-type allele in agreement with a classical two-hit inactivation. Global transcription analysis of KIF1Bβ mutant pheochromocytomas revealed that these tumors are transcriptionally related to pheochromocytomas with RET and NF1 mutations but independent from SDH- and VHL-associated tumors. Furthermore, KIF1Bβ-mutant tumors are uniquely enriched for pathways related to glutamate metabolism and the oxidative stress response. Our data start to delineate the signals that are disrupted by KIF1Bβ dysfunction in pheochromocytomas and suggest that loss of this gene may also be permissive to the development of nonneural crest malignancies. This may imply the existence of a tissue-specific gene dosage requirement for its tumorigenesis.
  Human Genetics 09/2008; 124(3):279-285. · 5.07 Impact Factor
• Article: Coordinated expression of microRNA-155 and predicted target genes in diffuse large B-cell lymphoma.

  Deepak Rai, Shailaja Karanti, Inkyung Jung, Patricia L M Dahia, Ricardo C T Aguiar
  [show abstract] [hide abstract]
  ABSTRACT: MicroRNAs (miRNAs) attenuate gene expression by pairing to the 3'UTR of target transcripts inducing RNA cleavage or translational inhibition. Overexpression of microRNA-155 (miR-155), measured either at the primary (BIC gene) or mature transcript level, was recently described in diffuse large B-cell lymphomas (DLBCL). These studies have been limited in size, however, and have not attempted to link miR-155 expression to that of putative target genes. To start to address these issues, we examined a collection of 22 well-characterized DLBCL cell lines. The expression of miR-155 is heterogeneous in these cell lines and associates with NF-kappaB activity. We found that the expression of the primary miR-155 transcript reliably reflects that of the functional mature miR-155. Because many gene array platforms include probe sets for the primary miR-155 sequences, these findings allowed us to confidently examine large array-based expression datasets of primary DLBCLs in the context of miR-155 levels. Our investigation revealed that miR-155 expression segregates with specific molecular subgroups of DLBCL and it is highest in activated B-cell (ABC)-type lymphomas. These tumors are characterized by constitutive activation of NF-kappaB signals, which supports the data derived from our cell lines. More importantly, using supervised learning algorithms, we identified a robust gene signature driven by the differential expression of miR-155. These profiles contained several gene markers, including predicted targets, consistently downregulated in tumors expressing high levels of miR-155. Our data start to unveil the genome-wide effects of miR-155 expression in DLBCL and indicate the utility of this strategy in the identification and validation of miRNA target genes.
  Cancer Genetics and Cytogenetics 03/2008; 181(1):8-15. · 1.39 Impact Factor
• Article: Germline mutation in the aryl hydrocarbon receptor interacting protein gene in familial somatotropinoma.

  Rodrigo A Toledo, Delmar M Lourenço, Bernardo Liberman, Malebranche B C Cunha-Neto, Maria G Cavalcanti, Cinthia B Moyses, Sergio P A Toledo, Patricia L M Dahia
  [show abstract] [hide abstract]
  ABSTRACT: Acromegaly is usually sporadic, but familial cases occur in association with several familial pituitary tumor syndromes. Recently mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene were associated with familial pituitary adenoma predisposition. The objective of the study was to investigate the status of AIP in a pituitary tumor predisposition family. The study was conducted at a nonprofit academic center and medical centers. Eighteen members of a Brazilian family with acromegaly were studied. A novel germline mutation in the AIP gene, Y268X, predicted to generate a protein lacking two conserved domains, was identified in four members of this family: two siblings with early-onset acromegaly; a third, 41-yr-old sibling with a microadenoma but no clinical features of disease, and his 3-yr-old son. No changes were found in 14 unaffected at-risk relatives or 92 healthy controls. We confirm the role of the AIP gene in familial acromegaly. This finding increases the spectrum of molecular defects that can give rise to pituitary adenoma susceptibility. Establishment of genotype-phenotype correlations in AIP mutant tumors will determine whether AIP screening can be used as a tool for clinical surveillance and genetic counseling of families with pituitary tumor predisposition. The underlying basis for the phenotypic variation within AIP-mutant families and the mechanism of AIP-mediated tumorigenesis remain to be defined.
  Journal of Clinical Endocrinology &amp Metabolism 06/2007; 92(5):1934-7. · 6.50 Impact Factor
• Article: Transcription association of VHL and SDH mutations link hypoxia and oxidoreductase signals in pheochromocytomas.

  Patricia L M Dahia
  [show abstract] [hide abstract]
  ABSTRACT: Pheochromocytomas and paragangliomas are neural-crest-derived tumors that arise from mutations in RET, VHL, NF1, and in the genes-encoding succinate dehydrogenase (SDH) subunits B (SDHB), C (SDHC), and D (SDHD). Despite their genetic diversity, these tumors cannot be clearly distinguished on the basis of their primary mutation. We recently identified two major transcriptional programs embedded within familial and sporadic pheochromocytomas and paragangliomas using global expression profiling. This review will summarize the major results of these studies and discuss their implications. The transcription data revealed that: (a) tumors with mutations in VHL, SDHB, and SDHD genes share a transcription signature of hypoxia, angiogenesis, and oxidoreductase imbalance; (b) SDHB protein is suppressed in tumors with mutations in SDHB and SDHD, and also in a subset of tumors with VHL mutations; and (c) HIF1alpha is involved in the SDHB downregulation observed in these tumors. These results are consistent with the existence of a close interconnection between the VHL and SDH pathways mediated predominantly by hypoxia and oxidoreductase signals. It further suggests that low SDHB levels indicative of impaired mitochondrial complex II function may be a shared element of these pheochromocytomas. SDHB may thus constitute a marker for tumors with abnormal hypoxic profile.
  Annals of the New York Academy of Sciences 09/2006; 1073:208-20. · 3.15 Impact Factor
• Source

  Available from: Janice Pasieka

  Article: Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.

  Diana E Benn, Anne-Paule Gimenez-Roqueplo, Jennifer R Reilly, Jérôme Bertherat, John Burgess, Karen Byth, Michael Croxson, Patricia L M Dahia, Marianne Elston, Oliver Gimm, [......], Philippe Herman, Victoria Murday, Patricia Niccoli-Sire, Janice L Pasieka, Vincent Rohmer, Kathy Tucker, Xavier Jeunemaitre, Deborah J Marsh, Pierre-François Plouin, Bruce G Robinson
  [show abstract] [hide abstract]
  ABSTRACT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations. Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations. The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland. Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined. SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008). For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.
  Journal of Clinical Endocrinology &amp Metabolism 04/2006; 91(3):827-36. · 6.50 Impact Factor
• Article: Evolving concepts in pheochromocytoma and paraganglioma.

  Patricia L M Dahia
  [show abstract] [hide abstract]
  ABSTRACT: The pheochromocytoma field has recently undergone a paradigm shift. This review will highlight some of these novel findings, including their impact on our understanding of the disease biology and influence on clinical management. Identification of novel susceptibility loci and recognition of a high rate of germline mutations in pheochromocytomas indicate that their genetic diversity is broader and more complex than previously estimated. Further, increased risk of tumor malignancy and aggressiveness in certain patients with succinate dehydrogenase subunit B(SDHB) mutations suggest that they may have prognostic value as predictors of pheochromocytoma behavior. Finally, discovery of a shared activation of the hypoxic response in pheochromocytomas with mutations in VHL and SDH genes and uncovering of a common JunB-mediated apoptosis defect in the major hereditary groups of pheochromocytoma have provided a mechanistic basis for the clinical similarities between these distinct syndromes. The notion that 'sporadic'-appearing tumors may in fact be components of one of multiple hereditary syndromes has a major impact on surveillance and follow-up of patients and their at-risk family members. Likewise, the ability to predict tumor malignancy has the potential to improve the prognosis of these patients. Importantly, insights into the biology of pheochromocytomas have provided clues on pathway interactions in cancers and have laid the ground for generation of new hypotheses on the cell-of-origin of these tumors. Pheochromocytomas have therefore emerged as key models for understanding cancer biology and for paving the way for future designer treatment in this and other cancers.
  Current Opinion in Oncology 02/2006; 18(1):1-8. · 4.10 Impact Factor
• Article: A RET mutation with decreased penetrance in the family of a patient with a "sporadic" pheochromocytoma.

  Seth M Arum, Patricia L M Dahia, Katherine Schneider, Lewis E Braverman
  [show abstract] [hide abstract]
  ABSTRACT: We present the case of a 38-yr-old man with a sporadic, multifocal pheochromocytoma and paraganglioma who was discovered to carry a Y791F germline mutation in exon 13 of the RET proto-oncogene. This mutation was found in his 65-yr-old mother and his 86-yr-old maternal grandmother. Neither of them had either biochemical evidence of pheochromocytoma or medullary thyroid carcinoma. The patient had a pro-phylactic thyroidectomy, which revealed mild C-cell hyperplasia. This case brings to discussion several issues: (1) the benefit of screening patients with apparently sporadic pheochromocytomas for genetic mutations; (2) the management of patients and families with "lower-risk" RET mutations; and (3) the possibility that lower-penetrance RET mutations may contribute to the list of causes of familial pheochromocytomas.
  Endocrine 12/2005; 28(2):193-8. · 1.42 Impact Factor
• Source

  Available from: harvard.edu

  Article: Novel pheochromocytoma susceptibility loci identified by integrative genomics.

  Patricia L M Dahia, Ke Hao, John Rogus, Christian Colin, Miguel A G Pujana, Ken Ross, Danielle Magoffin, Neil Aronin, Alberto Cascon, César Y Hayashida, Cheng Li, Sérgio P A Toledo, Charles D Stiles
  [show abstract] [hide abstract]
  ABSTRACT: Pheochromocytomas are catecholamine-secreting tumors that result from mutations of at least six different genes as components of distinct autosomal dominant disorders. However, there remain familial occurrences of pheochromocytoma without a known genetic defect. We describe here a familial pheochromocytoma syndrome consistent with digenic inheritance identified through a combination of global genomics strategies. Multipoint parametric linkage analysis revealed identical LOD scores of 2.97 for chromosome 2cen and 16p13 loci. A two-locus parametric linkage analysis produced maximum LOD score of 5.16 under a double recessive multiplicative model, suggesting that both loci are required to develop the disease. Allele-specific loss of heterozygosity (LOH) was detected only at the chromosome 2 locus in all tumors from this family, consistent with a tumor suppressor gene. Four additional pheochromocytomas with a similar genetic pattern were identified through transcription profiling and helped refine the chromosome 2 locus. High-density LOH mapping with single nucleotide polymorphism-based array identified a total of 18 of 62 pheochromocytomas with LOH within the chromosome 2 region, which further narrowed down the locus to <2 cM. This finding provides evidence for two novel susceptibility loci for pheochromocytoma and adds a recessive digenic trait to the increasingly broad genetic heterogeneity of these tumors. Similarly, complex traits may also be involved in other familial cancer syndromes.
  Cancer Research 11/2005; 65(21):9651-8. · 7.86 Impact Factor
• Source

  Available from: Vânia Nosé

  Article: A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas.

  Patricia L M Dahia, Ken N Ross, Matthew E Wright, César Y Hayashida, Sandro Santagata, Marta Barontini, Andrew L Kung, Gabriela Sanso, James F Powers, Arthur S Tischler, [......], Katherine Schneider, Judy Garber, Seth M Arum, Márta Korbonits, Ashley Grossman, Pascal Pigny, Sérgio P A Toledo, Vania Nosé, Cheng Li, Charles D Stiles
  [show abstract] [hide abstract]
  ABSTRACT: Pheochromocytomas are neural crest-derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1alpha. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors.
  PLoS Genetics 08/2005; 1(1):72-80. · 8.69 Impact Factor
• Article: Peptide hormone receptor defects leading to abnormal phenotypes

  Patricia L.M. Dahia, Sergio P.A. Toledo
  [show abstract] [hide abstract]
  ABSTRACT: In recent years, the molecular basis of several human disorders, especially endocrine diseases, has been increasingly unraveled. In many cases the defect has been recognized to result from abnormal structure of genes encoding for hormone receptors. Many syndromes of hormone resistance were found to result from an inability of the target receptor to perform its physiologic function, and the molecular defect responsible for such phenotypes has been found to reside in loss-of-function or inactivating mutations of the corresponding receptor gene. This has been shown to be the case for the luteinizing hormone, follicle-stimulating hormone, and estrogen receptors, to mention some of the most recently identified genes, and also for the longer established growth hormone, corticotropin, vaso pressin, and calcium-sensing receptor genes, among others. Mutations in all these genes have been shown to be involved in producing endocrine-resistant states. Identification and characterization of naturally occurring receptor mutations has contributed to our understanding not only of the molecular basis of endocrine diseases but also of the basic receptor signaling mechanisms and the physiology of hormone interactions. (C) Lippincott-Raven Publishers.
  Current Opinion in Endocrinology Diabetes and Obesity 03/1996; 3(2). · 3.62 Impact Factor