Genomic Medicine Institute and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Am J Hum Genet. 2013 Jan 10;92(1):76-80. doi: 10.1016/j.ajhg.2012.10.021. Epub 2012 Dec 13.
Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. Germline 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.
考登综合征（CS）是一种难以识别的多发性错构瘤综合征，具有较高的乳腺癌、甲状腺癌和其他癌症风险。在三级学术中心累积的资料显示，10q23 上的 PTEN 种系突变导致 85%的 CS，但过去 12 年来自社区的前瞻性累积资料显示，PTEN 突变频率为 25%。PTEN 是一种磷酸酶，与遗传性癌症综合征有关，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，并在细胞周期、迁移、细胞极性和细胞凋亡中发挥作用。我们报告称，在 91 名无种系 PTEN 突变的无关 CS 个体中，有 8 名（8.8%）携带 10 种种系 PIK3CA 突变（7 种错义突变、1 种无义突变和 2 种插入缺失）和 2 种 AKT1 突变。这些突变导致 P-Thr308-AKT 显著增加和细胞 PIP3 增加。我们的观察结果表明，PIK3CA 和 AKT1 是 CS 易感基因。
