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1. Data from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

Author

Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas

Abstract

Purpose: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers.Experimental Design: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic).Results: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Δβmetastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1–2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity.Conclusions: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases. Clin Cancer Res; 21(13); 3020–30. ©2015 AACR.

Published
2023

2. Supplemental Table 2 from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

Author

Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas

Abstract

Supplemental Table 2. Bisulfite pyrosequencing primer sequences.

Published
2023

3. Supplemental Table 1 from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

Author

Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas

Abstract

Supplemental Table 1. Detailed clinical data for PPGL samples.

Published
2023

4. supplemental legend from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

Author

Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas

Abstract

supplemental legend

Published
2023

5. Supplemental Figure 1 from DNA Methylation Profiling in Pheochromocytoma and Paraganglioma Reveals Diagnostic and Prognostic Markers

Author

Mercedes Robledo, Anne-Paule Gimenez-Roqueplo, Judith Favier, Mario F. Fraga, Cristina Rodríguez-Antona, Alberto Cascon, Ronald de Krijger, Felix Beuschlein, Henri Timmers, Guiseppe Opocher, Massimo Mannelli, Graeme Eisenhofer, Veronika Mancikova, Francesca Schiavi, Iñaki Comino-Méndez, Agustin F. Fernández, Maria Currás-Freixes, Eric Letouzé, Lucia Inglada-Pérez, Esther Korpershoek, and Aguirre A. de Cubas

Abstract

Supplemental Figure 1. PNMT gene methylation in PPGL.

Published
2023

6. Data from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Author

Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann

Abstract

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs ∼US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age ≤40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care. [Cancer Res 2009;69(8):3650–6]

Published
2023

7. Supplementary Table 1 Legends and References from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Author

Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann

Abstract

Supplementary Table 1 Legends and References from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Published
2023

8. Data from Novel Pheochromocytoma Susceptibility Loci Identified by Integrative Genomics

Author

Charles D. Stiles, Sérgio P.A. Toledo, Cheng Li, César Y. Hayashida, Alberto Cascon, Neil Aronin, Danielle Magoffin, Ken Ross, Miguel A.G. Pujana, Christian Colin, John Rogus, Ke Hao, and Patricia L.M. Dahia

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

Published
2023

10. Supplementary Table 1 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Author

Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann

Abstract

Supplementary Table 1 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Published
2023

11. Other Supporting Colleagues from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Author

Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann

Abstract

Other Supporting Colleagues from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Published
2023

12. Supplementary Table 2 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Author

Charis Eng, Carlos Suarez, Andrzej Januszewicz, Gerd J. Ridder, Giuseppe Opocher, Alberto Cascon, Klaus Zerres, Ulrich Finckh, Witold Szyfter, Matti Välimäki, Peter Schwerdtfeger, Sven Koscielny, Matthias Kühnemund, Alexander Glien, Christoph Brase, Jörg Schipper, Masoud Motasaddi Zarandy, Mahdi Malekpour, Harald Gorgulla, Christian Fottner, Timo Stöver, Holger Kaftan, Martin A. Walter, Dirk Eβer, Simon F. Preuss, Nicole Reisch, Christoph Matthias, Gerhard Dyckhoff, Michael Strohm, Stephan Knipping, Robert R. Lorenz, Mihaela Muresan, Wolfgang Draf, Svetlana Yaremchuk, Dmitry Zabolotny, Michael Croxson, Diana Learoyd, Robyn L. Ward, Pascal Pigny, Agata Kubaszek, Mariola Peczkowska, Marjan M. Weiss, Maria A. Sevilla, Maren Sullivan, Michael M. Hoffmann, Boris A. Stuck, Gerd Rasp, Stefanie Wiegand, Bruce G. Robinson, Diana E. Benn, Emily Edelman, Markus Fischer, Karen Lampe, Catherine Bauters, Pingling Kwok, Maurizio Falcioni, Francesca Schiavi, Mario Hermsen, Mercedes Robledo, Lisa A. Rybicki, Carsten C. Boedeker, Zoran Erlic, and Hartmut P.H. Neumann

Abstract

Supplementary Table 2 from Clinical Predictors for Germline Mutations in Head and Neck Paraganglioma Patients: Cost Reduction Strategy in Genetic Diagnostic Process as Fall-Out

Published
2023

13. International initiative for a curated

Author

Laurene, Ben Aim, Eamonn R, Maher, Alberto, Cascon, Anne, Barlier, Sophie, Giraud, Tonino, Ercolino, Pascal, Pigny, Roderick J, Clifton-Bligh, Delphine, Mirebeau-Prunier, Amira, Mohamed, Judith, Favier, Anne-Paule, Gimenez-Roqueplo, Francesca, Schiavi, Rodrigo A, Toledo, Patricia L, Dahia, Mercedes, Robledo, Jean Pierre, Bayley, and Nelly, Burnichon

Subjects
Paraganglioma, Succinate Dehydrogenase, Adrenal Gland Neoplasms, Humans, Genetic Testing, Pheochromocytoma, Germ-Line Mutation
Abstract

A total of 223 distinctThis multistep process resulted in 23 benign/likely benign, 149 pathogenic/likely pathogenic variants and 51 variants of unknown significance (VUS). Expert curation reduced by half the number of variants initially classified as VUS. Variant classifications are publicly accessible via the Leiden Open Variation Database system (https://databases.lovd.nl/shared/genes/SDHB).This international initiative by a panel of experts allowed us to establish a consensus classification for 223

Published
2020

14. DLST mutations in pheochromocytoma and paraganglioma cause proteome hyposuccinylation and metabolic remodeling

Author

Sara Mellid, Fernando García, Luis Javier Leandro‐García, Alberto Díaz‐Talavera, Ángel Mario Martínez‐Montes, Eduardo Gil, Bruna Calsina, María Monteagudo, Rocío Letón, Juan María Roldán‐Romero, María Santos, Javier Lanillos, Carlos Valdivia, Natalia Martínez‐Puente, Javier deNicolás‐Hernández, Scherezade Jiménez, Manuel Pérez‐Martínez, Emiliano Honrado, Javier Coloma, Ana Cerezo, Clara María Santiveri, Manel Esteller, Ramón Campos‐Olivas, Eduardo Caleiras, Cristina Montero‐Conde, Cristina Rodríguez‐Antona, Javier Muñoz, Mercedes Robledo, and Alberto Cascón

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2023
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15. Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency

Author

Gerardo G. Piroli, Allison M. Manuel, Richard S. McCain, Holland H. Smith, Oliver Ozohanics, Sara Mellid, J. Hunter Cox, William E. Cotham, Michael D. Walla, Alberto Cascón, Attila Ambrus, and Norma Frizzell

Subjects
Fumarate, Protein succination, Leigh syndrome, Complex I, Alpha-ketoglutarate dehydrogenase, Substrate level phosphorylation, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract

The NDUFS4 knockout (KO) mouse phenotype resembles the human Complex I deficiency Leigh Syndrome. The irreversible succination of protein thiols by fumarate is increased in select regions of the NDUFS4 KO brain affected by neurodegeneration. We report that dihydrolipoyllysine-residue succinyltransferase (DLST), a component of the α-ketoglutarate dehydrogenase complex (KGDHC) of the tricarboxylic acid (TCA) cycle, is succinated in the affected regions of the NDUFS4 KO brain. Succination of DLST reduced KGDHC activity in the brainstem (BS) and olfactory bulb (OB) of KO mice. The defective production of KGDHC derived succinyl-CoA resulted in decreased mitochondrial substrate level phosphorylation (SLP), further aggravating the existing oxidative phosphorylation (OXPHOS) ATP deficit. Protein succinylation, an acylation modification that requires succinyl-CoA, was reduced in the KO mice. Modeling succination of a cysteine in the spatial vicinity of the DLST active site or introduction of succinomimetic mutations recapitulates these metabolic deficits. Our data demonstrate that the biochemical deficit extends beyond impaired Complex I assembly and OXPHOS deficiency, functionally impairing select components of the TCA cycle to drive metabolic perturbations in affected neurons.

Published
2023
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16. Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

Author

Bruna Calsina, Elena Piñeiro-Yáñez, Ángel M. Martínez-Montes, Eduardo Caleiras, Ángel Fernández-Sanromán, María Monteagudo, Rafael Torres-Pérez, Coral Fustero-Torre, Marta Pulgarín-Alfaro, Eduardo Gil, Rocío Letón, Scherezade Jiménez, Santiago García-Martín, Maria Carmen Martin, Juan María Roldán-Romero, Javier Lanillos, Sara Mellid, María Santos, Alberto Díaz-Talavera, Ángeles Rubio, Patricia González, Barbara Hernando, Nicole Bechmann, Margo Dona, María Calatayud, Sonsoles Guadalix, Cristina Álvarez-Escolá, Rita M. Regojo, Javier Aller, Maria Isabel Del Olmo-Garcia, Adrià López-Fernández, Stephanie M. J. Fliedner, Elena Rapizzi, Martin Fassnacht, Felix Beuschlein, Marcus Quinkler, Rodrigo A. Toledo, Massimo Mannelli, Henri J. Timmers, Graeme Eisenhofer, Sandra Rodríguez-Perales, Orlando Domínguez, Geoffrey Macintyre, Maria Currás-Freixes, Cristina Rodríguez-Antona, Alberto Cascón, Luis J. Leandro-García, Cristina Montero-Conde, Giovanna Roncador, Juan Fernando García-García, Karel Pacak, Fátima Al-Shahrour, and Mercedes Robledo

Subjects
Science
Abstract

The molecular mechanisms underlying metastasis in pheochromocytoma/paraganglioma (mPPGL) remain to be explored. Here, the authors perform genomic and immunogenomic profiling of mPPGL tumors and suggest potential biomarkers for risk of metastasis and immunotherapy response.

Published
2023
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18. Co-occurrence of mutations in NF1 and other susceptibility genes in pheochromocytoma and paraganglioma

Author

Sara Mellid, Eduardo Gil, Rocío Letón, Eduardo Caleiras, Emiliano Honrado, Susan Richter, Nuria Palacios, Marcos Lahera, Juan C. Galofré, Adriá López-Fernández, Maria Calatayud, Aura D. Herrera-Martínez, María A. Galvez, Xavier Matias-Guiu, Milagros Balbín, Esther Korpershoek, Eugénie S. Lim, Francesca Maletta, Sofia Lider, Stephanie M. J. Fliedner, Nicole Bechmann, Graeme Eisenhofer, Letizia Canu, Elena Rapizzi, Irina Bancos, Mercedes Robledo, and Alberto Cascón

Subjects
pheochromocytoma, NF1, germline mutation, DLST, MDH2, co-occurrent mutations, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

IntroductionThe percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes.MethodsHerein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development.ResultsAmongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an “intermediate signature” to suggest that both variants had a pathological role in tumour development.DiscussionIn conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.

Published
2023
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20. Comprehensive molecular analysis of immortalization hallmarks in thyroid cancer reveals new prognostic markers

Author

Cristina Montero‐Conde, Luis Javier Leandro‐García, Ángel M. Martínez‐Montes, Paula Martínez, Francisco J. Moya, Rocío Letón, Eduardo Gil, Natalia Martínez‐Puente, Sonsoles Guadalix, Maria Currás‐Freixes, Laura García‐Tobar, Carles Zafon, Mireia Jordà, Garcilaso Riesco‐Eizaguirre, Patricia González‐García, María Monteagudo, Rafael Torres‐Pérez, Veronika Mancikova, Sergio Ruiz‐Llorente, Manuel Pérez‐Martínez, Guillermo Pita, Juan Carlos Galofré, Anna Gonzalez‐Neira, Alberto Cascón, Cristina Rodríguez‐Antona, Diego Megías, María A. Blasco, Eduardo Caleiras, Sandra Rodríguez‐Perales, and Mercedes Robledo

Subjects
5p‐end FISH, subtelomeric gene expression, telomere shortening, TERC, TERT promoter methylation, TERT promoter mutation, Medicine (General), R5-920
Abstract

Background Comprehensive molecular studies on tumours are needed to delineate immortalization process steps and identify sensitive prognostic biomarkers in thyroid cancer. Methods and Results In this study, we extensively characterize telomere‐related alterations in a series of 106 thyroid tumours with heterogeneous clinical outcomes. Using a custom‐designed RNA‐seq panel, we identified five telomerase holoenzyme‐complex genes upregulated in clinically aggressive tumours compared to tumours from long‐term disease‐free patients, being TERT and TERC denoted as independent prognostic markers by multivariate regression model analysis. Characterization of alterations related to TERT re‐expression revealed that promoter mutations, methylation and/or copy gains exclusively co‐occurred in clinically aggressive tumours. Quantitative‐FISH (fluorescence in situ hybridization) analysis of telomere lengths showed a significant shortening in these carcinomas, which matched with a high proliferative rate measured by Ki‐67 immunohistochemistry. RNA‐seq data analysis indicated that short‐telomere tumours exhibit an increased transcriptional activity in the 5‐Mb‐subtelomeric regions, site of several telomerase‐complex genes. Gene upregulation enrichment was significant for specific chromosome‐ends such as the 5p, where TERT is located. Co‐FISH analysis of 5p‐end and TERT loci showed a more relaxed chromatin configuration in short telomere‐length tumours compared to normal telomere‐length tumours. Conclusions Overall, our findings support that telomere shortening leads to a 5p subtelomeric region reorganization, facilitating the transcription and accumulation of alterations at TERT‐locus.

Published
2022
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21. Systematic comparison of sporadic and syndromic pancreatic islet cell tumors

Author

Zoran Erlic, Ursula Ploeckinger, Alberto Cascon, Michael M Hoffmann, Laura von Duecker, Aurelia Winter, Gerit Kammel, Janina Bacher, Maren Sullivan, Berend Isermann, Lars Fischer, Andreas Raffel, Wolfram Trudo Knoefel, Matthias Schott, Tobias Baumann, Oliver Schaefer, Tobias Keck, Richard P Baum, Ioana Milos, Mihaela Muresan, Mariola Peczkowska, Andrzej Januszewicz, Kenko Cupisti, Anke Tönjes, Mathias Fasshauer, Jan Langrehr, Peter von Wussow, Abbas Agaimy, Günter Schlimok, Regina Lamberts, Thorsten Wiech, Kurt Werner Schmid, Alexander Weber, Mercedes Nunez, Mercedes Robledo, Charis Eng, Hartmut P H Neumann, and University of Zurich

Subjects
Male, Oncology, Cancer Research, Pathology, von Hippel-Lindau Disease, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Medizin, Disease, Neuroendocrine tumors, urologic and male genital diseases, Polymerase Chain Reaction, Endocrinology, Germany, Prevalence, 1306 Cancer Research, Family history, Child, Multiple endocrine neoplasia, Aged, 80 and over, medicine.diagnostic_test, DNA, Neoplasm, Middle Aged, Adenoma, Islet Cell, female genital diseases and pregnancy complications, 1310 Endocrinology, Neuroendocrine Tumors, 2712 Endocrinology, Diabetes and Metabolism, Female, 2730 Oncology, Adult, medicine.medical_specialty, Adolescent, 610 Medicine & health, Malignancy, Young Adult, Germline mutation, Internal medicine, parasitic diseases, Multiple Endocrine Neoplasia Type 1, medicine, Humans, MEN1, neoplasms, Germ-Line Mutation, Aged, Genetic testing, business.industry, Genetic Variation, Sequence Analysis, DNA, medicine.disease, 10029 Clinic and Policlinic for Internal Medicine, business
Abstract

Pancreatic islet cell tumors (ICTs) occur as sporadic neoplasias or as a manifestation of multiple endocrine neoplasia type 1 (MEN1) and von Hippel–Lindau disease (VHL). Molecular classification of ICTs is mandatory for timely diagnosis and surveillance. Systematic comparison of VHL-ICTs and sporadic ICTs has been lacking. Our registry-based approaches used the German NET-Registry with 259 patients with neuroendocrine tumors (NETs), who were primarily diagnosed with NETs, and the German VHL-Registry with 485 molecular genetically confirmed patients who had undergone magnetic resonance imaging or computed tomography of the abdomen. All patients provided blood DNA for testing of the MEN1 and VHL genes for intragenic mutations and large deletions. In the NET-Registry, 9/101 patients (8.9%) with ICTs had germline mutations, 8 in MEN1 and 1 in VHL. In the VHL-Registry, prevalence of NETs was 52/487 (10.6%), and all were ICTs. Interestingly, of those with VHL p.R167W, 47% developed ICTs, compared to 2% of those with p.Y98H. In total, there were 92 truly sporadic, i.e. mutation-negative ICT patients. Comparing these with the 53 VHL-ICT patients, the statistically significant differences were predominance of female gender (P=0.01), multifocal ICTs (P=0.0029), and lower malignancy rate (PVHL gene, unless they have multifocal ICTs, other VHL-associated tumors, and/or a family history for VHL.

Published
2010

22. Advanced sporadic renal epithelioid angiomyolipoma: case report of an extraordinary response to sirolimus linked to TSC2 mutation

Author

Marta Espinosa, Juan Maria Roldán-Romero, Ignacio Duran, Enrique de Álava, María Apellaniz-Ruiz, Alberto Cascón, Carmen Garrigos, Mercedes Robledo, and Cristina Rodriguez-Antona

Subjects
Renal epithelioid angiomyolipoma, Sirolimus, TSC2 mutation, mTOR pathway activation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined. Case presentation Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation. Conclusion NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs.

Published
2018
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