Campbell Ian G, Russell Sarah E, Choong David Y H, Montgomery Karen G, Ciavarella Marianne L, Hooi Christine S F, Cristiano Briony E, Pearson Richard B, Phillips Wayne A
VBCRC Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Cancer Res. 2004 Nov 1;64(21):7678-81. doi: 10.1158/0008-5472.CAN-04-2933.
Phosphatidylinositol 3'-kinases are lipid kinases with important roles in neoplasia. Recently, a very high frequency of somatic mutations in PIK3CA has been reported among a large series of colorectal cancers. However, the relevance of PIK3CA mutation in other cancer types remains unclear because of the limited number of tumors investigated. We have screened a total of 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single stranded conformational polymorphism and denaturing high-performance liquid chromatography analysis. Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, grade or presence of tumor in lymph nodes. Among the primary epithelial ovarian cancers only 11 of 167 (6.6%) contain somatic mutations, but there was a clear histologic subtype bias in their distribution. Only 2 of 88 (2.3%) of serous carcinomas had PIK3CA mutations compared with 8 of 40 (20.0%) endometrioid and clear cell cancers, which was highly significant (P = 0.001). In contrast, PIK3CA gene amplification (>7-fold) was common among all histologic subtypes (24.5%) and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene amplification was detected in 30.5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer.
磷脂酰肌醇3'-激酶是一类在肿瘤形成中具有重要作用的脂质激酶。最近，在大量结直肠癌中报道了PIK3CA基因体细胞突变的高频率。然而，由于所研究肿瘤数量有限，PIK3CA突变在其他癌症类型中的相关性仍不清楚。我们使用单链构象多态性和变性高效液相色谱分析相结合的方法，对总共284例原发性人类肿瘤的PIK3CA所有编码外显子进行了突变筛查。在70例原发性乳腺癌中，40%（70例中的28例）存在PIK3CA突变，使其成为该癌症类型中迄今为止描述的最常见突变。突变与组织学亚型、雌激素受体状态、分级或淋巴结中肿瘤的存在无关。在原发性上皮性卵巢癌中，167例中只有11例（6.6%）含有体细胞突变，但它们的分布存在明显的组织学亚型偏向。浆液性癌88例中只有2例（2.3%）有PIK3CA突变，而子宫内膜样癌和透明细胞癌40例中有8例（20.0%），差异具有高度显著性（P = 0.001）。相反，PIK3CA基因扩增（>7倍）在所有组织学亚型中都很常见（24.5%），并且与突变的存在呈负相关。总体而言，在所有卵巢癌中30.5%检测到PIK3CA突变或基因扩增，在子宫内膜样癌和透明细胞亚型中为45%。我们的研究是PIK3CA是卵巢癌致癌基因的首个直接证据，并极大地扩展了最近在乳腺癌中的发现。
