Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas
Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas
复制标题
DOI：
10.1093/hmg/ddt639
复制
发表时间：
2014-05-01
影响因子：
3.5
通讯作者：
Gimenez-Roqueplo, Anne-Paule
中科院分区：
文献类型：
--
作者：
Castro-Vega, Luis Jaime;Buffet, Alexandre;Gimenez-Roqueplo, Anne-Paule
恶性嗜铬细胞瘤（PCC）和副神经节瘤（PGL）主要是由SDHB的种系突变引起的，SDHB编码琥珀酸脱氢酶的亚基。使用全外显子组测序，我们最近确定了突变FH基因编码富马酸水合酶，在PCC与SDH样分子表型。在这里，我们通过在一个大型国际患者队列中筛查生殖系FH突变，研究了FH在PCC/PGL易感性中的作用。我们筛选了598例已知PCC/PGL易感基因无突变的PCC/PGL患者。我们通过直接测序和多重连接依赖性探针扩增方法寻找FH种系突变和大缺失。通过免疫组织化学染色5-羟甲基胞嘧啶（5-hmC）和S-（2-琥珀酰）半胱氨酸（2SC），分别评估DNA甲基化和蛋白琥珀酸化的总体变化。我们在5名患者中发现了5种致病性生殖系FH突变（4种错义突变和1种剪接突变）。第二个等位基因的体细胞失活，导致富马酸水合酶活性的损失，在FH突变的肿瘤中得到证实。在FH突变的肿瘤中检测到低肿瘤水平的5-hmC，类似于SDHB缺陷型肿瘤中的5-hmC，以及阳性2SC染色。临床上，FH突变患者的转移表型（P 0.007）和多发性肿瘤（P 0.02）显著高于无此类突变的患者。这项研究揭示了FH在恶性和/或多发性PCC/PGL易感性中的新作用。值得注意的是，FH缺陷型PCC/PGL显示出与SDHB突变的恶性PCC/PGL相同的表观遗传失调模式。因此，我们建议FH的突变筛查应包括在PCC/PGL基因检测中，至少对于具有恶性行为的肿瘤。
Malignant pheochromocytoma (PCC) and paraganglioma (PGL) are mostly caused by germline mutations of SDHB, encoding a subunit of succinate dehydrogenase. Using whole-exome sequencing, we recently identified a mutation in the FH gene encoding fumarate hydratase, in a PCC with an SDH-like molecular phenotype. Here, we investigated the role of FH in PCC/PGL predisposition, by screening for germline FH mutations in a large international cohort of patients. We screened 598 patients with PCC/PGL without mutations in known PCC/PGL susceptibility genes. We searched for FH germline mutations and large deletions, by direct sequencing and multiplex ligation-dependent probe amplification methods. Global alterations in DNA methylation and protein succination were assessed by immunohistochemical staining for 5-hydroxymethylcytosine (5-hmC) and S-(2-succinyl) cysteine (2SC), respectively. We identified five pathogenic germline FH mutations (four missense and one splice mutation) in five patients. Somatic inactivation of the second allele, resulting in a loss of fumarate hydratase activity, was demonstrated in tumors with FH mutations. Low tumor levels of 5-hmC, resembling those in SDHB-deficient tumors, and positive 2SC staining were detected in tumors with FH mutations. Clinically, metastatic phenotype (P 0.007) and multiple tumors (P 0.02) were significantly more frequent in patients with FH mutations than those without such mutations. This study reveals a new role for FH in susceptibility to malignant and/or multiple PCC/PGL. Remarkably, FH-deficient PCC/PGLs display the same pattern of epigenetic deregulation as SDHB-mutated malignant PCC/PGL. Therefore, we propose that mutation screening for FH should be included in PCC/PGL genetic testing, at least for tumors with malignant behavior.