嗜铬细胞瘤和副神经节瘤(PPGL)是罕见的神经内分泌肿瘤,具有25-40%的致病性种系基因变异(PGV)。我们评估了临床,实验室,在我们机构随访的115例病理证实PPGL的患者(14例患者是来自8个不同家庭的亲属进行基因调查)和生殖系分子谱。具有经典MEN2A/MEN2B表型和危险亲属的患者接受了RET原癌基因的直接分析,其余的样本提交给完成针对23个PPGL相关基因的下一代测序:ATM,ATR,CDKN2A,EGLN1,FH,HRAS,KIF1B,KMT2D,MAX,MDH2、MERTK、MET,NF1,PIK3CA,RET,SDHA,SDHAF2,SDHB,SDHC,SDHD,TMEM127、TP53和VHL。我们还开发了临床判断评分(CJS)来确定患者患有潜在遗传性疾病的概率。由此产生的遗传景观显示,67名患者(58.3%)在至少一个基因中存在变异:34名(50.7%)仅具有致病性或可能的致病性变异,13(19.4%)有致病性或可能的致病性变异和未确定意义的变异(VUS),和20(29.8%)只携带VUS。在RET中发现PGV(n=18;38.3%),VHL(n=10;21.3%),SDHB和NF1(n=8;各17%),MAX,SDHD,TMEM127和TP53(n=1;各2.1%)。直接基因检测显示91.3%的敏感性,81.2%的特异性,76.4%和93.3%的阳性预测值(PPV)和阴性预测值(NPV),分别。识别不会从基因检测中受益的患者的CJS敏感性为75%,96.4%的特异性,以及60%和98.2%的PPV和NPV,分别。总之,来自115名巴西患者的PPGL种系基因变异的景观导致了稍高的流行致病性和可能的致病性变异,尤其是RET基因。我们建议使用CJS来识别不需要初始遗传评估的PPGL患者,提高测试的特异性和降低成本。
Pheochromocytoma and paragangliomas (PPGLs) are rare neuroendocrine tumors carrying 25-40% pathogenic germline gene variants (PGVs). We evaluated clinical, laboratory, and germline molecular profile of 115 patients with pathologic (14 patients were relatives from 8 different families recruited for genetic survey) confirmed PPGL followed in our institution. Patients with classic MEN2A/MEN2B phenotypes and at-risk relatives underwent direct analysis of RET proto-oncogene, and the remaining had samples submitted to complete next-generation sequencing aiming 23 PPGL-related genes: ATM, ATR, CDKN2A, EGLN1, FH, HRAS, KIF1B, KMT2D, MAX, MDH2, MERTK, MET, NF1, PIK3CA, RET, SDHA, SDHAF2,
SDHB, SDHC, SDHD, TMEM127, TP53, and VHL. We also developed a clinical judgment score (CJS) to determine the probability of patients having a potentially hereditary disease. The resulting genetic landscape showed that 67 patients (58.3%) had variants in at least one gene: 34 (50.7%) had exclusively pathogenic or likely pathogenic variants, 13 (19.4%) had pathogenic or likely pathogenic variants and variant of undetermined significance (VUS), and 20 (29.8%) carried only VUS. PGVs were found in RET (n = 18; 38.3%), VHL (n = 10; 21.3%),
SDHB and NF1 (n = 8; 17% each), and MAX, SDHD, TMEM127, and TP53 (n = 1; 2.1% each). Direct genetic testing disclosed 91.3% sensitivity, 81.2% specificity, and 76.4% and 93.3% positive predictive value (PPV) and negative predictive values (NPV), respectively. The CJS to identify patients who would not benefit from genetic testing had 75% sensitivity, 96.4% specificity, and 60% and 98.2% PPV and NPV, respectively. In summary, the landscape of PPGL germline gene variants from 115 Brazilian patients resulted in slightly higher prevalent pathogenic and likely pathogenic variants, especially in the RET gene. We suggest a CJS to identify PPGL patients who would not require initial genetic evaluation, improving test specificity and reducing costs.