Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients
Recommendations for somatic and germline genetic testing of single pheochromocytoma and paraganglioma based on findings from a series of 329 patients
复制标题
DOI：
10.1136/jmedgenet-2015-103218
复制
发表时间：
2015-10-01
影响因子：
4
通讯作者：
Robledo, Mercedes
中科院分区：
文献类型：
--
作者：
Curras-Freixes, Maria;Inglada-Perez, Lucia;Robledo, Mercedes
背景目前，65-80%的嗜铬细胞瘤和副神经节瘤(PPGL)病例由22个基因中的一个基因的种系或体细胞突变所解释。已经提出了几种基因检测算法，但它们通常排除散发性PPGL(S-PPGLS)，没有一种包括体细胞检测。方法对329例符合3个标准的S-PPGL先证者进行基因检测，包括：单一PPGL、无综合征和无PPGL家族史。胚系DNA检测RET的点突变，VHL、SDH基因、TMEM127、MAX和FH的点突变和总缺失。结果发现46例(14.0%)患者存在胚系突变，其中副神经节瘤(PGLS)的发生率(28.7%)明显高于嗜铬细胞瘤(PCCs)(4.5%)(p=6.62×10(-10))。43%的受试者发现了体细胞突变，PCCs(48.5%)高于PGL(32.3%)(p=0.13)。四分之一的S-PPGL有体细胞突变，与出现时的年龄无关。头颈部PGLS(HN-PGLS)和胸椎PGLS(T-PGLS)的胚系突变更常见(p=2.0x10(-4)和p=0.027)。29例转移病例中有5例存在体细胞突变，1例发生在HRAS。结论我们建议优先检测HN-PGLS和TPGLS患者的种系突变，以及PCC患者的体细胞突变。生化分泌物和SDHB免疫组织化学可指导腹型PGLS的基因筛查。儿科和转移性病例不应被排除在躯体筛查之外。
Background Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source.Methods The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB.Results Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p= 6.62x10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p= 0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p= 2.0x10(-4) and p= 0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS.Conclusions We recommend prioritising testing for germline mutations in patients with HN-PGLs and TPGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.