PIK3CA alterations in Middle Eastern ovarian cancers.
PIK3CA alterations in Middle Eastern ovarian cancers.
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DOI：
10.1186/1476-4598-8-51
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发表时间：
2009-07-28
期刊：
影响因子：
37.3
通讯作者：
Al-Kuraya KS
中科院分区：
文献类型：
--
作者：
Abubaker J;Bavi P;Al-Haqawi W;Jehan Z;Munkarah A;Uddin S;Al-Kuraya KS
PI3K/AKT信号通路在多种恶性肿瘤的细胞生长、增殖和肿瘤发生中发挥重要作用。该信号通路已被证明在包括卵巢癌在内的几种人类癌症中经常发生改变。然而，这种致癌信号通路在中东上皮性卵巢癌（EOC）中的作用尚未得到探索。因此，我们在 156 个 EOC 中研究了 PI3K/AKT 基因改变，如 PIK3CA 扩增、PIK3CA 突变、PTEN 蛋白丢失及其与各种临床病理特征的关系。荧光原位杂交（FISH）技术和DNA测序分别用于分析PIK3CA扩增和突变。通过免疫组织化学分析PIK3CA蛋白表达(p110α)、PTEN、p-AKT和Ki-67的表达。在分析的 152 例 EOC 病例中，有 54 例 (35.5%) 发现 PIK3CA 扩增； 6/153 EOC（3.9%）中PIK3CA基因突变； 3/154 EOC 中出现 KRAS 突变（1.9%），3/156 EOC 中出现 BRAF 突变（1.9%），50/154 EOC 中出现 p53 突变（32.5%），33/144 EOC 中出现 PTEN 蛋白表达缺失（22.9%）。 p110 α 过表达与 AKT-Ser 473 磷酸化增加和增殖标记物 Ki-67 相关。我们的数据显示 PIK3CA 扩增的分子事件与 PIK3CA、KRAS、BRAF 基因突变之间的相互排斥性，这表明这些改变中的每一个可能足以独立驱动卵巢肿瘤的发病机制。中东卵巢癌中 PI3K/AKT 通路遗传改变的高发生率提供了遗传证据，支持 PI3K/AKT 通路失调在卵巢癌发病机制中发挥重要作用的观点。
PI3K/AKTsignaling pathway plays an important role in cell growth, proliferation, and tumorgenesis of various malignancies. This signaling pathway has been shown to be frequently altered in several human cancers including ovarian cancers. However the role of this oncogenic signaling pathway has not been explored in the Middle Eastern epithelial ovarian cancer (EOC). Therefore, we investigated PI3K/AKT genetic alterations such as PIK3CA amplification, PIK3CA mutation, PTEN protein loss and their relationships with various clinicopathological characteristics in 156 EOCs. Fluorescence in situ hybridization (FISH) technique and DNA sequencing were used to analyze PIK3CA amplification and mutation respectively. Expression of PIK3CA protein expression (p110 α), PTEN, p-AKT and Ki-67 was analyzed by immunohistochemistry. PIK3CA amplification was seen in 54 of 152 (35.5%) EOC cases analyzed; PIK3CA gene mutations in 6/153 EOC (3.9%); KRAS mutations in 3/154 EOC (1.9%), BRAF mutations in 3/156 EOC (1.9%), p53 mutation in 50/154 EOC (32.5%), and loss of PTEN protein expression in 33/144 EOC (22.9%). p110 α overexpression was associated with increased phosphorylation of AKT-Ser 473 and with the proliferation marker Ki-67. Our data showed mutual exclusivity between the molecular event of PIK3CA amplification and mutations in PIK3CA, KRAS, BRAF genes, which suggests that each of these alterations may individually be sufficient to drive ovarian tumor pathogenesis independently. High prevalence of genetic alterations in PI3K/AKT pathway in a Middle Eastern ovarian carcinoma provides genetic evidence supporting the notion that dysregulated PI3K/AKT pathways play an important role in the pathogenesis of ovarian cancers.
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