Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes
Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes
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DOI：
10.1016/j.ajhg.2012.10.021
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发表时间：
2013-01-10
影响因子：
9.8
通讯作者：
Eng, Charis
中科院分区：
文献类型：
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作者：
Orloff, Mohammed S.;He, Xin;Eng, Charis
考登综合征(CS)是一种难以识别的多发性错构瘤综合征，具有乳腺癌、甲状腺和其他癌症的高风险。研究发现，PTEN基因10q23上的胚系突变导致85%的CS来自高等教育中心，但过去12年来自社区的预期收益显示，PTEN突变频率为25%。PTEN是一种磷酸酶，它与一种可遗传的癌症综合征有关，并随后与多种散发性癌症和发育过程有关。PTEN拮抗AKT1/PI3K信号通路，在细胞周期、迁移、细胞极性和细胞凋亡中发挥作用。我们报告了91例无胚系PTEN突变的无亲缘关系的CS患者中有8例(8.8%)携带10个胚系PIK3CA突变(7个错义突变、1个无义突变和2个插入突变)和2个AKT1突变(2.2%)。这些突变导致P-Thr308-AKT显著增加，细胞内PIP3增加。我们的观察结果提示PIK3CA和AKT1是CS的易感基因。
Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. Germ line mutations in PTEN on 10q23 were found to cause 85% of CS when accrued from tertiary academic centers, but prospective accrual from the community over the last 12 years has revealed a 25% PTEN mutation frequency. PTEN is the phosphatase that has been implicated in a heritable cancer syndrome and subsequently in multiple sporadic cancers and developmental processes. PTEN antagonizes the AKT1/PI3K signaling pathway and has roles in cell cycle, migration, cell polarity, and apoptosis. We report that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations (7 missense, 1 nonsense, and 2 indels) and 2 (2.2%) AKT1 mutations. These mutations result in significantly increased P-Thr308-AKT and increased cellular PIP3. Our observations suggest that PIK3cA and AKT1 are CS susceptibility genes.