Phosphatidylinositol 3-kinase mutations associated with ovarian, colon and breast tumours

结直肠癌和乳腺癌是澳大利亚最常见的两种可登记的癌症，在每年癌症死亡总数中仅次于肺癌（1997年结直肠癌和乳腺癌死亡人数分别为4 678人和2 612人）。每年还有740名妇女死于卵巢癌（资料来源：1997年澳大利亚癌症，澳大利亚卫生健康研究院和澳大利亚癌症研究院，2000年）。因此，平均每小时就有一名澳大利亚人死于结直肠癌、乳腺癌或卵巢癌！显然，这些都是对我们社会产生重大影响的主要疾病。不幸的是，我们仍然不了解导致这些癌症发生的基本分子和生化异常。最近对许多不同类型肿瘤（包括结肠癌和卵巢癌）的功能和遗传学研究表明，磷脂酰肌醇3-激酶（PI3K）酶家族的成员可能是致癌基因（致癌基因）。然而，尚未有强有力的证据证实PI3K在人类癌症中的因果作用。我们的研究计划概述了一项研究来解决这个问题。我们有初步的数据表明，在许多肿瘤中，至少有一种酶家族的成员发生了突变。我们现在建议对发生在结肠、乳腺和卵巢肿瘤中的PI3K突变的频谱和频率进行全面分析。这些研究将使我们能够对PI3K在人类癌症发展中的作用做出明确的评估。除了进一步加深我们对人类肿瘤发生和发展过程的理解外，该项目还具有确定癌症早期检测的新标志物和新的抗癌疗法的新靶点的潜力。

Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact on our society. Unfortunately, though, we still do not understand the basic molecular and-or biochemical abnormalities that initiate and-or drive the development of these cancers. Recent functional and genetic studies in a number of different tumour types (including colon and ovarian) have suggested that members of the phosphatidylinositol 3-kinase (PI3K) enzyme family may be oncogenes (cancer-causing genes). However, strong evidence confirming a causal role for PI3K in human cancer is yet to be reported. Our research proposal outlines a study to address this issue. We have preliminary data demonstrating mutations in at least one member of this enzyme family in a number of tumours. We now propose to undertake a comprehensive analysis of the spectrum, and frequency, of PI3K mutations that occur in colon, breast and ovarian tumours. These studies will allow us to make a definitive assessment of the role of PI3K in the development human cancer. In addition to furthering our understanding of the processes involved in the initiation and progression of human tumours, this project also has the potential to identify new markers for the early detection of cancer and novel targets for new anti-cancer therapies.