MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma

Nelly Burnichon, Alberto Cascoń, 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 CorssmitMara Giacchè, Ronald R. De Krijger, Tonino Ercolino, Xavier Girerd, Encarna B. Gómez-Garćia, Álvaro Gómez-Graña, Isabelle Guilhem, Frederik J. Hes, Emiliano Honrado, Esther Korpershoek, Jacques W M Lenders, Rocío Letón, Arjen R. Mensenkamp, Anna Merlo, Luigi Mori, Arnaud Murat, Peggy Pierre, Pierre François Plouin, Tamara Prodanov, Miguel Quesada-Charneco, Nan Qin, Elena Rapizzi, Victoria Raymond, Nicole Reisch, Giovanna Roncador, Macarena Ruiz-Ferrer, Frank Schillo, Alexander P A Stegmann, Carlos Suarez, Elisa Taschin, Henri J L M Timmers, Carli M J Tops, Miguel Urioste, Felix Beuschlein, Karel Pacak, Massimo Mannelli, Patricia L Dahia, Giuseppe Opocher, Graeme Eisenhofer, Anne Paule Gimenez-Roqueplo, Mercedes Robledo

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2828-2837
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number10
DOIs
StatePublished - May 15 2012

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Paraganglioma
Factor X
Pheochromocytoma
Mutation
Germ-Line Mutation
Neoplasms
Normetanephrine
Metanephrine
Glandular and Epithelial Neoplasms
Neural Crest
Multiplex Polymerase Chain Reaction
Tumor Suppressor Genes
Referral and Consultation
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Burnichon, N., Cascoń, A., Schiavi, F., Morales, N., Comino-Méndez, I., Abermil, N., ... Robledo, M. (2012). MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clinical Cancer Research, 18(10), 2828-2837. https://doi.org/10.1158/1078-0432.CCR-12-0160

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. / Burnichon, Nelly; Cascoń, Alberto; Schiavi, Francesca; Morales, NicolePaes; Comino-Méndez, Iñaki; Abermil, Nasséra; Inglada-Pérez, Lucía; De Cubas, Aguirre A.; Amar, Laurence; Barontini, Marta; De Quiroś, Sandra Bernaldo; Bertherat, Jérôome; Bignon, Yves Jean; Blok, Marinus J.; Bobisse, Sara; Borrego, Salud; Castellano, Maurizio; Chanson, Philippe; Chiara, María Dolores; Corssmit, Eleonora P M; Giacchè, Mara; De Krijger, Ronald R.; Ercolino, Tonino; Girerd, Xavier; Gómez-Garćia, Encarna B.; Gómez-Graña, Álvaro; Guilhem, Isabelle; Hes, Frederik J.; Honrado, Emiliano; Korpershoek, Esther; Lenders, Jacques W M; Letón, Rocío; Mensenkamp, Arjen R.; Merlo, Anna; Mori, Luigi; Murat, Arnaud; Pierre, Peggy; Plouin, Pierre François; Prodanov, Tamara; Quesada-Charneco, Miguel; Qin, Nan; Rapizzi, Elena; Raymond, Victoria; Reisch, Nicole; Roncador, Giovanna; Ruiz-Ferrer, Macarena; Schillo, Frank; Stegmann, Alexander P A; Suarez, Carlos; Taschin, Elisa; Timmers, Henri J L M; Tops, Carli M J; Urioste, Miguel; Beuschlein, Felix; Pacak, Karel; Mannelli, Massimo; Dahia, Patricia L; Opocher, Giuseppe; Eisenhofer, Graeme; Gimenez-Roqueplo, Anne Paule; Robledo, Mercedes.

In: Clinical Cancer Research, Vol. 18, No. 10, 15.05.2012, p. 2828-2837.

Research output: Contribution to journalArticle

Burnichon, N, Cascoń, A, Schiavi, F, Morales, N, Comino-Méndez, I, Abermil, N, Inglada-Pérez, L, De Cubas, AA, Amar, L, Barontini, M, De Quiroś, SB, Bertherat, J, Bignon, YJ, Blok, MJ, Bobisse, S, Borrego, S, Castellano, M, Chanson, P, Chiara, MD, Corssmit, EPM, Giacchè, M, De Krijger, RR, Ercolino, T, Girerd, X, Gómez-Garćia, EB, Gómez-Graña, Á, Guilhem, I, Hes, FJ, Honrado, E, Korpershoek, E, Lenders, JWM, Letón, R, Mensenkamp, AR, Merlo, A, Mori, L, Murat, A, Pierre, P, Plouin, PF, Prodanov, T, Quesada-Charneco, M, Qin, N, Rapizzi, E, Raymond, V, Reisch, N, Roncador, G, Ruiz-Ferrer, M, Schillo, F, Stegmann, APA, Suarez, C, Taschin, E, Timmers, HJLM, Tops, CMJ, Urioste, M, Beuschlein, F, Pacak, K, Mannelli, M, Dahia, PL, Opocher, G, Eisenhofer, G, Gimenez-Roqueplo, AP & Robledo, M 2012, 'MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma', Clinical Cancer Research, vol. 18, no. 10, pp. 2828-2837. https://doi.org/10.1158/1078-0432.CCR-12-0160
Burnichon N, Cascoń A, Schiavi F, Morales N, Comino-Méndez I, Abermil N et al. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clinical Cancer Research. 2012 May 15;18(10):2828-2837. https://doi.org/10.1158/1078-0432.CCR-12-0160
Burnichon, Nelly ; Cascoń, Alberto ; Schiavi, Francesca ; Morales, NicolePaes ; Comino-Méndez, Iñaki ; Abermil, Nasséra ; Inglada-Pérez, Lucía ; De Cubas, Aguirre A. ; Amar, Laurence ; Barontini, Marta ; De Quiroś, Sandra Bernaldo ; Bertherat, Jérôome ; Bignon, Yves Jean ; Blok, Marinus J. ; Bobisse, Sara ; Borrego, Salud ; Castellano, Maurizio ; Chanson, Philippe ; Chiara, María Dolores ; Corssmit, Eleonora P M ; Giacchè, Mara ; De Krijger, Ronald R. ; Ercolino, Tonino ; Girerd, Xavier ; Gómez-Garćia, Encarna B. ; Gómez-Graña, Álvaro ; Guilhem, Isabelle ; Hes, Frederik J. ; Honrado, Emiliano ; Korpershoek, Esther ; Lenders, Jacques W M ; Letón, Rocío ; Mensenkamp, Arjen R. ; Merlo, Anna ; Mori, Luigi ; Murat, Arnaud ; Pierre, Peggy ; Plouin, Pierre François ; Prodanov, Tamara ; Quesada-Charneco, Miguel ; Qin, Nan ; Rapizzi, Elena ; Raymond, Victoria ; Reisch, Nicole ; Roncador, Giovanna ; Ruiz-Ferrer, Macarena ; Schillo, Frank ; Stegmann, Alexander P A ; Suarez, Carlos ; Taschin, Elisa ; Timmers, Henri J L M ; Tops, Carli M J ; Urioste, Miguel ; Beuschlein, Felix ; Pacak, Karel ; Mannelli, Massimo ; Dahia, Patricia L ; Opocher, Giuseppe ; Eisenhofer, Graeme ; Gimenez-Roqueplo, Anne Paule ; Robledo, Mercedes. / MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 10. pp. 2828-2837.
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title = "MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma",
abstract = "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.",
author = "Nelly Burnichon and Alberto Cascoń and Francesca Schiavi and NicolePaes Morales and I{\~n}aki Comino-M{\'e}ndez and Nass{\'e}ra Abermil and Luc{\'i}a Inglada-P{\'e}rez and {De Cubas}, {Aguirre A.} and Laurence Amar and Marta Barontini and {De Quiroś}, {Sandra Bernaldo} and J{\'e}r{\^o}ome Bertherat and Bignon, {Yves Jean} and Blok, {Marinus J.} and Sara Bobisse and Salud Borrego and Maurizio Castellano and Philippe Chanson and Chiara, {Mar{\'i}a Dolores} and Corssmit, {Eleonora P M} and Mara Giacch{\`e} and {De Krijger}, {Ronald R.} and Tonino Ercolino and Xavier Girerd and G{\'o}mez-Garćia, {Encarna B.} and {\'A}lvaro G{\'o}mez-Gra{\~n}a and Isabelle Guilhem and Hes, {Frederik J.} and Emiliano Honrado and Esther Korpershoek and Lenders, {Jacques W M} and Roc{\'i}o Let{\'o}n and Mensenkamp, {Arjen R.} and Anna Merlo and Luigi Mori and Arnaud Murat and Peggy Pierre and Plouin, {Pierre Fran{\cc}ois} and Tamara Prodanov and Miguel Quesada-Charneco and Nan Qin and Elena Rapizzi and Victoria Raymond and Nicole Reisch and Giovanna Roncador and Macarena Ruiz-Ferrer and Frank Schillo and Stegmann, {Alexander P A} and Carlos Suarez and Elisa Taschin and Timmers, {Henri J L M} and Tops, {Carli M J} and Miguel Urioste and Felix Beuschlein and Karel Pacak and Massimo Mannelli and Dahia, {Patricia L} and Giuseppe Opocher and Graeme Eisenhofer and Gimenez-Roqueplo, {Anne Paule} and Mercedes Robledo",
year = "2012",
month = "5",
day = "15",
doi = "10.1158/1078-0432.CCR-12-0160",
language = "English (US)",
volume = "18",
pages = "2828--2837",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "10",

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TY - JOUR

T1 - MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma

AU - Burnichon, Nelly

AU - Cascoń, Alberto

AU - Schiavi, Francesca

AU - Morales, NicolePaes

AU - Comino-Méndez, Iñaki

AU - Abermil, Nasséra

AU - Inglada-Pérez, Lucía

AU - De Cubas, Aguirre A.

AU - Amar, Laurence

AU - Barontini, Marta

AU - De Quiroś, Sandra Bernaldo

AU - Bertherat, Jérôome

AU - Bignon, Yves Jean

AU - Blok, Marinus J.

AU - Bobisse, Sara

AU - Borrego, Salud

AU - Castellano, Maurizio

AU - Chanson, Philippe

AU - Chiara, María Dolores

AU - Corssmit, Eleonora P M

AU - Giacchè, Mara

AU - De Krijger, Ronald R.

AU - Ercolino, Tonino

AU - Girerd, Xavier

AU - Gómez-Garćia, Encarna B.

AU - Gómez-Graña, Álvaro

AU - Guilhem, Isabelle

AU - Hes, Frederik J.

AU - Honrado, Emiliano

AU - Korpershoek, Esther

AU - Lenders, Jacques W M

AU - Letón, Rocío

AU - Mensenkamp, Arjen R.

AU - Merlo, Anna

AU - Mori, Luigi

AU - Murat, Arnaud

AU - Pierre, Peggy

AU - Plouin, Pierre François

AU - Prodanov, Tamara

AU - Quesada-Charneco, Miguel

AU - Qin, Nan

AU - Rapizzi, Elena

AU - Raymond, Victoria

AU - Reisch, Nicole

AU - Roncador, Giovanna

AU - Ruiz-Ferrer, Macarena

AU - Schillo, Frank

AU - Stegmann, Alexander P A

AU - Suarez, Carlos

AU - Taschin, Elisa

AU - Timmers, Henri J L M

AU - Tops, Carli M J

AU - Urioste, Miguel

AU - Beuschlein, Felix

AU - Pacak, Karel

AU - Mannelli, Massimo

AU - Dahia, Patricia L

AU - Opocher, Giuseppe

AU - Eisenhofer, Graeme

AU - Gimenez-Roqueplo, Anne Paule

AU - Robledo, Mercedes

PY - 2012/5/15

Y1 - 2012/5/15

N2 - 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.

AB - 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.

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

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