Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention,JAMA Oncology

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Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention
JAMA Oncology ( IF 28.4 ) Pub Date : 2017-09-01 , DOI: 10.1001/jamaoncol.2017.0223
Birke Bausch ₁ , Francesca Schiavi ₂ , Ying Ni ₃ , Jenny Welander ₄ , Attila Patocs _{5,

6} , Joanne Ngeow ₇ , Ulrich Wellner ₈ , Angelica Malinoc ₉ , Elisa Taschin ₂ , Giovanni Barbon ₂ , Virginia Lanza ₂ , Peter Söderkvist ₄ , Adam Stenman ₁₀ , Catharina Larsson ₁₀ , Fredrika Svahn ₁₀ , Jin-Lian Chen ₃ , Jessica Marquard ₃ , Merav Fraenkel ₁₁ , Martin A Walter ₁₂ , Mariola Peczkowska ₁₃ , Aleksander Prejbisz ₁₃ , Barbara Jarzab ₁₄ , Kornelia Hasse-Lazar ₁₄ , Stephan Petersenn ₁₅ , Lars C Moeller ₁₆ , Almuth Meyer ₁₇ , Nicole Reisch ₁₈ , Arnold Trupka ₁₉ , Christoph Brase ₂₀ , Matthias Galiano ₂₁ , Simon F Preuss ₂₂ , Pingling Kwok ₂₃ , Nikoletta Lendvai ₆ , Gani Berisha ₉ , Özer Makay ₂₄ , Carsten C Boedeker ₂₅ , Georges Weryha ₂₆ , Karoly Racz ₅ , Andrzej Januszewicz ₁₃ , Martin K Walz ₂₇ , Oliver Gimm _{4,

28} , Giuseppe Opocher ₂ , Charis Eng ₂₉ , Hartmut P H Neumann ₃₀ ,

Affiliation

Department of Medicine II, Freiburg University Medical Center, Albert-Ludwigs University, Freiburg, Germany.
Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Second Department of Medicine, Semmelweis University, Budapest, Hungary.
Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary.
Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre Singapore and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
Department of Surgery, University of Lübeck, Lübeck, Germany.
Department of Nephrology and General Medicine, University Medical Center, Albert-Ludwigs University, Freiburg, Germany.
Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital Stockholm, Stockholm, Sweden.
Department of Medicine, Endocrinology, and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Institute of Nuclear Medicine, University Hospital, Bern, Switzerland.
Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.
Center for Endocrine Tumors, Hamburg, Germany.
Department of Endocrinology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
Department of Endocrinology, Helios Klinikum, Erfurt, Germany.
Department of Endocrinology, Ludwigs-Maximilians University of Munich, Munich, Germany.
Department of Surgery, City Hospital, Starnberg, Germany.
Department of Otorhinolaryngology, University of Erlangen, Erlangen, Germany.
Department of Pediatrics and Adolescent Medicine, University Hospital of Erlangen, Erlangen, Germany.
Department of Otolaryngology, University of Cologne, Cologne, Germany.
Department of Otorhinolaryngology, University of Regensburg, Regensburg, Germany.
Division of Endocrine Surgery, Department of General Surgery, Ege University, Izmir, Turkey.
Department of Otolaryngology, HELIOS Hanseklinikum Stralsund, Stralsund, Germany.
Department of Endocrinology, University of Nancy, Nancy, France.
Department of Surgery and Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany.
Department of Surgery, Region Östergötland, Linköping, Sweden.
Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
Section for Preventive Medicine, University Medical Center, Albert-Ludwigs University, Freiburg, Germany.

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.

中文翻译：

用于基因知情预防的嗜铬细胞瘤和副神经节瘤易感基因 SDHA、TMEM127、MAX 和 SDHAF2 的临床特征

重要性 有效的癌症预防基于准确的分子诊断和遗传家族筛查结果、基于基因型的风险评估以及为早期诊断量身定制的策略。遗传性嗜铬细胞瘤和副神经节瘤的病因不断扩大，最近包括SDHA、TMEM127、MAX和SDHAF2作为易感基因。缺乏针对这 4 个新纳入基因的种系突变患者的临床管理指南。

目的研究SDHA、TMEM127、MAX和SDHAF2基因突变个体的临床谱和年龄相关外显率。

设计、设置和患者本研究分析了 1993 年至 2016 年SDHA、TMEM127、MAX和SDHAF2种系突变携带者的前瞻性、纵向随访的欧洲-美国-亚洲嗜铬细胞瘤-副神经节瘤登记处的患病率。基因预测测试和临床调查由向突变阳性登记者及其亲属提供从颈部到骨盆的成像，以临床表征与 4 个新基因突变相关的嗜铬细胞瘤/副神经节瘤疾病。

主要结果和措施评估了 SDHA、TMEM127、MAX和SDHAF2基因种系突变的患病率和谱。对SDHA、TMEM127、MAX和SDHAF2疾病的临床特征进行了表征。

结果 972 名无典型嗜铬细胞瘤和副神经节瘤相关基因突变的无关登记者（632 名女性 [65.0%] 和 340 名男性 [35.0%]；年龄范围，8-80 岁；平均 [SD] 年龄，41.0 [13.3] 岁） )，58 个 (6.0%) 携带感兴趣的种系突变，包括 29个 SDHA、 20 个TMEM127、8个MAX和 1 个SDHAF2。58 名患者中有 53 名 (91%) 患有家族性、多发性、肾上腺外和/或恶性肿瘤和/或年龄小于 40 岁。新发现的是SDHA和TMEM127疾病中的 63 例 (11%) 恶性嗜铬细胞瘤和副神经节瘤中的7 例。SDHA该病早在8岁时就发生了。28 名突变携带者（48%）和 29名 SDHA突变携带者中的 23 名（79%）发生肾上腺外肿瘤，尤其是头颈部副神经节瘤。MAX病几乎只发生在肾上腺，常伴有双侧肿瘤。最大子集SDHA携带者的外显率在 40 岁时为 39%，并且在指数患者 (45%) 与携带突变的亲属 (13%; P < .001) 中存在统计学差异。