Tissue-specific genetic interactions in cancer

项目总结/摘要 在过去十年中，基因组测序技术的进步提供了一个 全面调查导致癌症的体细胞突变。大肠癌 (CRC)是美国癌症相关死亡的第三大常见原因，全基因组 测序鉴定APC、KRAS和PIK 3CA为三种最常见的突变基因。 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，特别是在特定突变体水平上， 等位基因精准医疗，医生根据患者的基因量身定制治疗方案， 在他/她的癌症突变，需要这种水平的理解，因为激活状态的 精确药物靶向的致癌信号通路依赖于 而不是单个基因的突变。一个很好的例子 这一概念涉及KRAS，其中激活性错义突变发生在40%的CRC中。 在这40%的CRC中，KRAS突变的多样性大于任何其他类型的CRC。 癌我们假设CRCs可能选择在其他癌症中缺失或罕见的KRAS等位基因， 癌症，因为与突变APC的遗传相互作用，这在CRC中几乎无处不在， 但在其他癌症中更罕见。此外，除了APC，最常见的共突变基因 与KRAS的突变是PIK 3CA，但PIK 3CA突变仅与KRAS的特定等位基因共同发生。 基于我们在使用基因工程研究癌症遗传学方面的专业知识， 小鼠模型，并基于我们对动物工程的广泛初步分析， 在结肠中表达突变形式的K-Ras，我们将进行深入的遗传研究， CRC中癌症基因之间的相互作用。这项工作分为两个具体目标：（1） 为了确定APC和HSP 70之间遗传相互作用的分子机制， KRAS和（2）了解为什么PIK 3CA突变优先发生在特定的KRAS中 CRC中的等位基因。最后，这项研究将为遗传相互作用提供关键的见解， 发生在CRC中，并可能揭示针对表达 突变型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.