Tissue-specific genetic interactions in cancer

项目摘要/摘要 在过去的十年中，基因组测序技术的进步提供了一种 对导致癌症的体细胞突变进行全面调查。在结直肠癌中 (CRC)，全基因组范围内，美国与癌症相关的死亡的第三大常见原因 测序证实APC、KRAS和PIK3CA是三个最常见的突变基因。 然而，大规模的全基因组测序工作并不能提供足够的粒度 关于突变基因之间的相互作用，特别是在特定突变水平上的相互作用 等位基因。精确医学，即医生根据患者的基因量身定做治疗 在他/她的癌症中发生突变，需要这种水平的理解，因为 精确药物靶向的致癌信号通路依赖于全息图 癌症中的基因变化，而不是单个基因的突变。一个典型的例子 这个概念与KRAS有关，在KRAS中，激活错义突变发生在40%的CRC中。 在这40%的癌中，KRAS突变的多样性比任何其他类型的癌都要大 癌症。我们推测，CRC可能选择了KRAS等位基因，这些等位基因在其他基因中不存在或罕见 癌症是因为与突变的APC的基因相互作用，这种突变在结直肠癌中几乎无处不在， 但在其他癌症中更为罕见。此外，除APC外，该基因最常见的是共突变 与KRAS相关的是PIK3CA，但PIK3CA突变仅与KRAS的特定等位基因共发生。 基于我们在研究癌症遗传学方面的专业知识，使用基因工程技术 小鼠模型，并基于我们对经过工程改造的动物的广泛初步分析 在结肠中表达突变形式的K-RAS，我们将对遗传学进行深入的研究 结直肠癌中肿瘤基因间的相互作用。这项工作分为两个具体目标：(1) 为了确定APC和APC之间遗传相互作用的分子机制 KRAS和(2)了解为什么特定KRAS优先发生PIK3CA突变 结直肠癌的等位基因。最后，这项研究将提供对基因相互作用的关键见解 发生在结直肠癌中，并可能揭示针对表达基因的癌症的等位基因特异性治疗方法 突变的KRAS。

Project Summary/Abstract Advances in genome sequencing technologies over the past decade have provided a comprehensive survey of the somatic mutations that contribute to cancer. In colorectal cancer (CRC), the 3rd most common cause of cancer-related death in the United States, genome-wide sequencing identified APC, KRAS, and PIK3CA as three of the most commonly mutated genes. Nevertheless, large-scale, genome-wide sequencing efforts do not provide sufficient granularity with respect to the interactions between mutant genes, especially at the level of specific mutant alleles. Precision medicine, where a physician tailors a patient's therapy to the genes that are mutated in his/her cancer, requires this level of understanding because the activation state of oncogenic signaling pathways targeted by precision medicines is dependent upon the panoply of genetic changes in a cancer rather than on mutations in individual genes. A case-in-point of this concept relates to KRAS, in which activating missense mutations occur in 40% of CRCs. Among those 40% of CRCs, the diversity of KRAS mutations is greater than in any other type of cancer. We hypothesize that CRCs might select for KRAS alleles that are absent or rare in other cancers because of a genetic interaction with mutant APC, which is nearly ubiquitous in CRC, but rarer in other cancers. Moreover, aside from APC, the gene most commonly co-mutated with KRAS is PIK3CA, yet PIK3CA mutations co-occur only with specific alleles of KRAS. Building upon our expertise in studying the genetics of cancer using genetically engineered mouse models, and based on our extensive preliminary analysis of animals engineered to express mutant forms of K-Ras in the colon, we will perform an in-depth study of genetic interactions between cancer genes in CRC. This work is separated into two specific aims: (1) To determine the molecular mechanism underlying the genetic interaction between APC and KRAS and (2) To understand why PIK3CA mutations occur preferentially with specific KRAS alleles in CRC. In the end, this study will provide key insights into the genetic interactions that occur in CRC and may reveal allele-specific therapeutic approaches for cancers expressing mutant KRAS.