Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis
Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis
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DOI：
10.1093/hmg/ddt069
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发表时间：
2013-06-01
影响因子：
3.5
通讯作者：
Cascon, Alberto
中科院分区：
文献类型：
--
作者：
Comino-Mendez, Inaki;de Cubas, Aguirre A.;Cascon, Alberto
嗜铬细胞瘤（PCC）和副神经节瘤（PGL）是分别来自肾上腺髓质和肾上腺外副神经节的嗜铬细胞肿瘤。参与对缺氧的细胞应答的基因（例如VHL、EGL九同源物1和琥珀酸脱氢酶（SDH）基因）的功能障碍导致缺氧诱导因子（HIF）降解的直接废除，从而导致与PCC/PGL发展有关的假缺氧状态。最近，EPAS 1（HIF 2A）的体细胞合子后突变已被发现在多个PGLs和先天性红细胞增多症患者。我们评估了41例PCC/PGL的EPAS 1突变，并在此描述了7例发现携带体细胞EPAS 1突变的患者的临床、分子和遗传特征; 4例表现为多发性PGL（其中3例还患有先天性红细胞增多症），而3例为单发散发性PCC/PGL病例。EPAS 1突变肿瘤的基因表达分析显示，与SDH基因和VHL突变病例中发现的mRNA EPAS 1水平相似，并且两个缺氧诱导基因（PCSK 6和GNA 14）显著上调。有趣的是，单核苷酸多态性阵列分析显示，在三个EPAS 1突变的肿瘤中，染色体2 p的独家获得。此外，多重PCR筛选小重排检测到一个特定的EPAS 1增益在另一个EPAS 1突变的肿瘤和三个非EPAS 1突变的情况下。EPAS 1参与散发性疾病的发现不仅增加了具有已知驱动突变的PCC/PGLs的百分比，而且还突出了研究明显散发性肿瘤中其他缺氧相关基因的相关性。最后，在EPAS 1突变的肿瘤中检测到影响染色体2 p的特定拷贝数改变可能会指导这种疾病患者的遗传诊断。
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.