Biological and clinical characterisation of human phosphatidylinositide 3-kinase mutations

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。我们的实验室最近报道了在乳腺、结直肠和卵巢肿瘤中磷酸肌肽3-激酶（PI3K）基因PIK3CA的高频率突变。这项由NHMRC资助的工作不仅证实了PI3K是一个真正的人类致癌基因，而且证实了PI3K基因家族的突变是人类实体肿瘤中最常见的基因突变之一，因此可能是最重要的遗传异常之一。在目前的提案中，我们的目标是通过解决我们已经确定的突变的生物学后果和临床意义来扩展和补充我们的遗传研究。这将为人类肿瘤发生的生物学提供重要的新见解，并进一步加深我们对人类肿瘤发生和发展的关键途径和过程的理解。这些知识将帮助我们识别新的标志物，用于癌症的诊断、预后和早期发现，并使我们能够合理地设计新的抗癌疗法。

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. Our laboratory has recently reported a high frequency of mutation of the phosphoinositide 3-kinase (PI3K) gene PIK3CA in breast, colorectal and ovarian tumours. This work, funded by the NHMRC, has not only confirmed that PI3K is a bone fide human oncogene but also that mutations in the PI3K family of genes are one of the most common, and thus potentially one of the most important, genetic abnormalities in solid human tumours. In the current proposal, we aim to extend and complement our genetic studies by addressing the biological consequences and clinical significance of the mutations we have identified. This will provide crucial new insights into the biology of human tumourigenesis and further our understanding of the critical pathways and processes involved in the initiation and progression of human tumours. Such knowledge will help us to identify novel markers for diagnosis, prognosis and the early detection of cancer and enable a rational approach to the design of new anti-cancer therapies.