Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention

Birke Bausch, Francesca Schiavi, Ying Ni, Jenny Welander, Attila Patocs, Joanne Ngeow, Ulrich Wellner, Angelica Malinoc, Elisa Taschin, Giovanni Barbon, Virginia Lanza, Peter Söderkvist, Adam Stenman, Catharina Larsson, Fredrika Svahn, Jin Lian Chen, Jessica Marquard, Merav Fraenkel, Martin A. Walter, Mariola PeczkowskaAleksander Prejbisz, Barbara Jarzab, Kornelia Hasse-Lazar, Stephan Petersenn, Lars C. Moeller, Almuth Meyer, Nicole Reisch, Arnold Trupka, Christoph Brase, Matthias Galiano, Simon F. Preuss, Pingling Kwok, Nikoletta Lendvai, Gani Berisha, Özer Makay, Carsten C. Boedeker, Georges Weryha, Karoly Racz, Andrzej Januszewicz, Martin K. Walz, Oliver Gimm, Giuseppe Opocher, Charis Eng, Hartmut P.H. Neumann, European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Original languageEnglish
Pages (from-to)1204-1212
Number of pages9
JournalJAMA oncology
Volume3
Issue number9
DOIs
Publication statusPublished - Sep 1 2017

Fingerprint

Paraganglioma
Pheochromocytoma
Mutation
Germ-Line Mutation
Genes
Genetic Testing
Penetrance
Neck
Neoplasms
Glandular and Epithelial Neoplasms
Asian Americans
Adrenal Glands
Pelvis
Registries
Early Diagnosis
Head
Genotype
Outcome Assessment (Health Care)
Prospective Studies
Guidelines

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bausch, B., Schiavi, F., Ni, Y., Welander, J., Patocs, A., Ngeow, J., ... European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group (2017). Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. JAMA oncology, 3(9), 1204-1212. https://doi.org/10.1001/jamaoncol.2017.0223

Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. / Bausch, Birke; Schiavi, Francesca; Ni, Ying; Welander, Jenny; Patocs, Attila; Ngeow, Joanne; Wellner, Ulrich; Malinoc, Angelica; Taschin, Elisa; Barbon, Giovanni; Lanza, Virginia; Söderkvist, Peter; Stenman, Adam; Larsson, Catharina; Svahn, Fredrika; Chen, Jin Lian; Marquard, Jessica; Fraenkel, Merav; Walter, Martin A.; Peczkowska, Mariola; Prejbisz, Aleksander; Jarzab, Barbara; Hasse-Lazar, Kornelia; Petersenn, Stephan; Moeller, Lars C.; Meyer, Almuth; Reisch, Nicole; Trupka, Arnold; Brase, Christoph; Galiano, Matthias; Preuss, Simon F.; Kwok, Pingling; Lendvai, Nikoletta; Berisha, Gani; Makay, Özer; Boedeker, Carsten C.; Weryha, Georges; Racz, Karoly; Januszewicz, Andrzej; Walz, Martin K.; Gimm, Oliver; Opocher, Giuseppe; Eng, Charis; Neumann, Hartmut P.H.; European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group.

In: JAMA oncology, Vol. 3, No. 9, 01.09.2017, p. 1204-1212.

Research output: Contribution to journalArticle

Bausch, B, Schiavi, F, Ni, Y, Welander, J, Patocs, A, Ngeow, J, Wellner, U, Malinoc, A, Taschin, E, Barbon, G, Lanza, V, Söderkvist, P, Stenman, A, Larsson, C, Svahn, F, Chen, JL, Marquard, J, Fraenkel, M, Walter, MA, Peczkowska, M, Prejbisz, A, Jarzab, B, Hasse-Lazar, K, Petersenn, S, Moeller, LC, Meyer, A, Reisch, N, Trupka, A, Brase, C, Galiano, M, Preuss, SF, Kwok, P, Lendvai, N, Berisha, G, Makay, Ö, Boedeker, CC, Weryha, G, Racz, K, Januszewicz, A, Walz, MK, Gimm, O, Opocher, G, Eng, C, Neumann, HPH & European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group 2017, 'Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention', JAMA oncology, vol. 3, no. 9, pp. 1204-1212. https://doi.org/10.1001/jamaoncol.2017.0223
Bausch, Birke ; Schiavi, Francesca ; Ni, Ying ; Welander, Jenny ; Patocs, Attila ; Ngeow, Joanne ; Wellner, Ulrich ; Malinoc, Angelica ; Taschin, Elisa ; Barbon, Giovanni ; Lanza, Virginia ; Söderkvist, Peter ; Stenman, Adam ; Larsson, Catharina ; Svahn, Fredrika ; Chen, Jin Lian ; Marquard, Jessica ; Fraenkel, Merav ; Walter, Martin A. ; Peczkowska, Mariola ; Prejbisz, Aleksander ; Jarzab, Barbara ; Hasse-Lazar, Kornelia ; Petersenn, Stephan ; Moeller, Lars C. ; Meyer, Almuth ; Reisch, Nicole ; Trupka, Arnold ; Brase, Christoph ; Galiano, Matthias ; Preuss, Simon F. ; Kwok, Pingling ; Lendvai, Nikoletta ; Berisha, Gani ; Makay, Özer ; Boedeker, Carsten C. ; Weryha, Georges ; Racz, Karoly ; Januszewicz, Andrzej ; Walz, Martin K. ; Gimm, Oliver ; Opocher, Giuseppe ; Eng, Charis ; Neumann, Hartmut P.H. ; European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group. / Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. In: JAMA oncology. 2017 ; Vol. 3, No. 9. pp. 1204-1212.
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title = "Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention",
abstract = "IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0{\%}] and 340 male [35.0{\%}]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0{\%}) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91{\%}) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11{\%}) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48{\%}) and in 23 of 29 SDHA mutation carriers (79{\%}), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39{\%} at 40 years of age and is statistically different in index patients (45{\%}) vs mutation-carrying relatives (13{\%}; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.",
author = "Birke Bausch and Francesca Schiavi and Ying Ni and Jenny Welander and Attila Patocs and Joanne Ngeow and Ulrich Wellner and Angelica Malinoc and Elisa Taschin and Giovanni Barbon and Virginia Lanza and Peter S{\"o}derkvist and Adam Stenman and Catharina Larsson and Fredrika Svahn and Chen, {Jin Lian} and Jessica Marquard and Merav Fraenkel and Walter, {Martin A.} and Mariola Peczkowska and Aleksander Prejbisz and Barbara Jarzab and Kornelia Hasse-Lazar and Stephan Petersenn and Moeller, {Lars C.} and Almuth Meyer and Nicole Reisch and Arnold Trupka and Christoph Brase and Matthias Galiano and Preuss, {Simon F.} and Pingling Kwok and Nikoletta Lendvai and Gani Berisha and {\"O}zer Makay and Boedeker, {Carsten C.} and Georges Weryha and Karoly Racz and Andrzej Januszewicz and Walz, {Martin K.} and Oliver Gimm and Giuseppe Opocher and Charis Eng and Neumann, {Hartmut P.H.} and {European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group}",
year = "2017",
month = "9",
day = "1",
doi = "10.1001/jamaoncol.2017.0223",
language = "English",
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journal = "JAMA oncology",
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publisher = "American Medical Association",
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TY - JOUR

T1 - Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention

AU - Bausch, Birke

AU - Schiavi, Francesca

AU - Ni, Ying

AU - Welander, Jenny

AU - Patocs, Attila

AU - Ngeow, Joanne

AU - Wellner, Ulrich

AU - Malinoc, Angelica

AU - Taschin, Elisa

AU - Barbon, Giovanni

AU - Lanza, Virginia

AU - Söderkvist, Peter

AU - Stenman, Adam

AU - Larsson, Catharina

AU - Svahn, Fredrika

AU - Chen, Jin Lian

AU - Marquard, Jessica

AU - Fraenkel, Merav

AU - Walter, Martin A.

AU - Peczkowska, Mariola

AU - Prejbisz, Aleksander

AU - Jarzab, Barbara

AU - Hasse-Lazar, Kornelia

AU - Petersenn, Stephan

AU - Moeller, Lars C.

AU - Meyer, Almuth

AU - Reisch, Nicole

AU - Trupka, Arnold

AU - Brase, Christoph

AU - Galiano, Matthias

AU - Preuss, Simon F.

AU - Kwok, Pingling

AU - Lendvai, Nikoletta

AU - Berisha, Gani

AU - Makay, Özer

AU - Boedeker, Carsten C.

AU - Weryha, Georges

AU - Racz, Karoly

AU - Januszewicz, Andrzej

AU - Walz, Martin K.

AU - Gimm, Oliver

AU - Opocher, Giuseppe

AU - Eng, Charis

AU - Neumann, Hartmut P.H.

AU - European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group

PY - 2017/9/1

Y1 - 2017/9/1

N2 - IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

AB - IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

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