Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention
Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention
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DOI：
10.1001/jamaoncol.2017.0223
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发表时间：
2017-09-01
期刊：
影响因子：
28.4
通讯作者：
Neumann, Hartmut P. H.
中科院分区：
文献类型：
--
作者：
Bausch, Birke;Schiavi, Francesca;Neumann, Hartmut P. H.
重要的是，有效的癌症预防是基于准确的分子诊断和基因家系筛查的结果、基因信息的风险评估和定制的早期诊断策略。遗传性嗜铬细胞瘤和副神经节瘤的扩展病因学最近包括SDHA、TMEM127、MAX和SDHAF2等易感基因。目的研究SDHA、TMEM127、MAX和SDHAF2基因突变个体的临床谱系和年龄相关外显性。设计、背景和患者本研究分析了1993-2016年间欧洲-美国-亚洲嗜铬细胞瘤-副神经节瘤登记中SDHA、TMEM127、MAX和SDHAF2种系突变携带者的患病率。对突变阳性的登记者及其亲属进行从颈部到骨盆的基因预测测试和临床调查，以确定与4个新基因突变相关的嗜铬细胞瘤/副神经节瘤疾病的临床特征。评估SDHA、TMEM127、MAX和SDHAF2基因胚系突变的发生率和谱。结果972名无典型嗜铬细胞瘤和副神经节细胞瘤相关基因突变的非亲缘关系注册者(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名(6.0%)携带有感兴趣的种系突变，包括29名SDHA，20名TMEM127，8名MAX和1名SDHAF2。58例患者中有53例(91%)有家族性、多发性、肾上腺外和/或恶性肿瘤和/或年龄在40岁以下。新发现的63例恶性嗜铬细胞瘤和副神经节瘤中有7例(11%)在SDHA和TMEM127病中。SDHA病最早发生于8岁。肾上腺外肿瘤发生在28名突变携带者(48%)和29名SDHA突变携带者中的23名(79%)，尤其是头颈部副神经节瘤。Max病几乎完全发生在肾上腺，常为双侧肿瘤。SDHA携带者在40岁时的外显率为39%，与携带突变的亲属(13%；P<；.001)相比，差异有统计学意义。结论SDHA、TMEM127、MAX和SDHAF2基因可能与遗传性嗜铬细胞瘤和副神经节细胞瘤有关。如果经典基因突变为阴性，建议对临床高危患者进行基因检测。基因特异性预防和/或早期发现需要定期、系统的全身检查。
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.