DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.
DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.
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胰腺神经内分泌肿瘤中经常改变DAXX/ATRX，MEN1和MTOR途径基因。
DOI：
10.1126/science.1200609
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发表时间：
2011-03-04
期刊：
影响因子：
--
通讯作者：
Papadopoulos N
中科院分区：
文献类型：
--
作者：
Jiao Y;Shi C;Edil BH;de Wilde RF;Klimstra DS;Maitra A;Schulick RD;Tang LH;Wolfgang CL;Choti MA;Velculescu VE;Diaz LA Jr;Vogelstein B;Kinzler KW;Hruban RH;Papadopoulos N
胰腺神经内分泌肿瘤（PanNET）是一种罕见但临床上重要的胰腺肿瘤。为了探索PanNET的遗传基础，我们确定了10个非家族性PanNET的外显子组序列，然后筛选了另外58个PanNET中最常见的突变基因。值得注意的是，最频繁突变的基因指定了与染色质重塑有关的蛋白质：44%的肿瘤在MEN-1中有体细胞失活突变，MEN-1编码组蛋白甲基转移酶复合物的一种成分menin; 43%的人在编码DAXX组成的转录/染色质重塑复合物的两个亚基中的任何一个的基因中有突变，（死亡结构域相关蛋白）和ATRX（α地中海贫血/精神发育迟滞综合征X连锁）。临床上，MEN 1和DAXX/ATRX基因突变与更好的预后相关。我们还在14%的肿瘤中发现了mTOR（雷帕霉素的哺乳动物靶标）通路中的基因突变，这一发现可能用于对mTOR抑制剂治疗的患者进行分层。
Pancreatic Neuroendocrine Tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of ten non-familial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. Remarkably, the most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN-1, which encodes menin, a component of a histone methyltransferase complex; and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.
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