Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.
Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.
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DOI：
10.1126/science.1196333
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发表时间：
2010-10-08
期刊：
影响因子：
--
通讯作者：
Papadopoulos N
中科院分区：
文献类型：
--
作者：
Jones S;Wang TL;Shih IeM;Mao TL;Nakayama K;Roden R;Glas R;Slamon D;Diaz LA Jr;Vogelstein B;Kinzler KW;Velculescu VE;Papadopoulos N
卵巢透明细胞癌（OCCC）是一种侵袭性人类癌症，通常对治疗具有抗性。为了探索OCCC的遗传起源，我们在免疫亲和纯化癌细胞后确定了8种肿瘤的外显子序列。通过对来自相同患者的正常细胞的比较分析，我们确定了至少在两种肿瘤中发生突变的四种基因。PIK 3CA编码磷脂酰肌醇-3激酶的一个亚基，KRAS编码一种众所周知的癌蛋白，此前曾与OCCC有关。另外两个突变基因是新的：PPP 2 R1 A编码丝氨酸/苏氨酸磷酸酶2的调节亚基，ARID 1A编码富含AT的相互作用结构域的蛋白1A，其参与染色质重塑。突变的性质和模式表明PPP 2 R1 A作为癌基因发挥作用，ARID 1A作为肿瘤抑制基因发挥作用。在总共42例OCCC中，7%的人在PPP 2 R1 A中有突变，57%的人在ARID 1A中有突变。这些结果表明异常的染色质重塑有助于OCCC的发病机制。
Ovarian Clear Cell Carcinoma (OCCC) is an aggressive human cancer that is generally resistant to therapy. To explore the genetic origin of OCCC, we determined the exomic sequences of eight tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, we identified four genes that were mutated in at least two tumors. PIK3CA, which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS, which encodes a well known oncoprotein, had previously been implicated in OCCC. The other two mutated genes were novel: PPP2R1A encodes a regulatory subunit of serine/threonine phosphatase 2 and ARID1A encodes AT-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. In a total of 42 OCCCs, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. These results suggest that aberrant chromatin remodeling contributes to the pathogenesis of OCCC.
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