Germ-line mutations in nonsyndromic pheochromocytoma.
Germ-line mutations in nonsyndromic pheochromocytoma.
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DOI：
10.1056/nejmoa020152
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发表时间：
2002-05-09
影响因子：
158.5
通讯作者：
Eng, C
中科院分区：
文献类型：
--
作者：
Neumann, HPH;Bausch, B;Eng, C
背景：包括原癌基因 RET（与 2 型多发性内分泌肿瘤 [MEN-2] 相关）和肿瘤抑制基因 VHL（与 von Hippel-Lindau 病相关）在内的嗜铬细胞瘤易感基因组现在还包括新鉴定的琥珀酸脱氢酶亚基 D (SDHD) 和琥珀酸脱氢酶亚基 B (SDHB) 基因，这些基因使携带者易患嗜铬细胞瘤和血管球瘤。我们使用分子工具根据这四个基因之一是否存在突变对一大群嗜铬细胞瘤患者进行分类，并研究遗传分析与临床实践的相关性。方法：对来自无关、同意登记的嗜铬细胞瘤患者的外周血进行 RET、VHL、SDHD 和 SDHB 突变检测。对首次就诊和随访时的临床数据进行了评估。结果：在 271 名无症状性嗜铬细胞瘤且无该病家族史的患者中，66 名（24%）被发现有突变（平均年龄 25 岁；32 名男性和 34 名女性）。在这 66 例中，30 例有 VHL 突变，13 例有 RET 突变，11 例有 SDHD 突变，12 例有 SDHB 突变。年龄较小、多灶性肿瘤和肾上腺外肿瘤与突变的存在显着相关。然而，在 66 名突变阳性患者中，只有 21 名患有多灶性嗜铬细胞瘤。 23 例（35%）在 30 岁之后出现，17 例（8%）在 40 岁之后出现。61 例（92%）携带突变的患者仅通过 VHL、RET、SDHD 和 SDHB 分子检测来识别；这些患者在就诊时没有相关体征和症状。结论：几乎四分之一的明显散发性嗜铬细胞瘤患者可能是突变携带者；对 RET、VHL、SDHD 和 SDHB 突变的常规分析可识别嗜铬细胞瘤相关综合征，否则可能会被遗漏。
Background: The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice.Methods: Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated.Results: Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation.Conclusions: Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.