The mechanism of cancer-specific allele selection for K-RAS

项目概要/摘要 ** RAS癌基因中的激活突变在癌症中发现，并有助于恶性肿瘤的发生。 通过正常增殖和分化的失调来改变表型。作为测序数据， 癌症基因组变得可用，很明显，激活Ras突变可以在许多癌症中发现。 不同的氨基酸此外，特定Ras突变的分布和它们发生的同种型 随组织类型而高度变化，表明Ras驱动的肿瘤发生机制取决于组织- 特殊的基因相互作用。在上皮癌中，结肠直肠癌（CRC）是独特的，因为它富含 K-Ras的罕见等位基因，如K-RasA 146 T和K-RasG 13 D。CRC和其他上皮性癌之间的一个关键区别 癌症（如胰腺癌或肺癌）是Apc的丢失，因此Wnt信号传导的激活非常频繁， 并且通常是肿瘤发生所必需的。我们实验室的初步证据显示，在结肠中，K-RasA 146 T，K- RasG 13 D和K-RasG 12 D表达表现为不同的表型，具有不同的Ras活化水平。 然而，在Apc丢失的背景下，因此在CRC中，K-Ras的较弱等位基因（G13 D和A146 T） 现在被过度激活，并且在表型上与K-RasG 12 D无法区分。我假设Apc的缺失， 因此Wnt信号的激活，可能通过改变K-Ras的基因， 调节K-Ras的GTP酶激活蛋白（GAP）的表达。我建议在以下几个方面来检验这个假设： 小鼠结肠类器官，使用已建立的方法从外部调节Wnt水平，并观察这如何影响 在各种突变等位基因的背景下K-Ras活化。此外，使用现有的条件鼠标 这些K-Ras突变体等位基因的模型，我将表征他们的表型和分子特性， 胰腺，并确定该组织中Wnt信号传导的缺乏是否有助于富集某些亚组的 突变。这项研究的结果将有助于建立组织特异性遗传的重要性， K-Ras的相互作用-一个重要的研究领域，使用精准医学来设计治疗策略 靶向K-Ras突变型癌症。

Project Summary/Abstract** Activating mutations in the RAS oncogenes are found across cancers, and contribute to a malignant phenotype through deregulation of normal proliferation and differentiation. As sequencing data from whole cancer genomes becomes available, it has become apparent that activating Ras mutations can be found at many different amino acids. Moreover, the distribution of specific Ras mutations and the isoform in which they occur vary highly with tissue type, suggesting that the mechanism for Ras-driven oncogenesis depends on tissue- specific genetic interactions. Among epithelial cancers, colorectal cancer (CRC) is unique in that it enriches for the rarer alleles of K-Ras, such as K-RasA146T and K-RasG13D. A key difference between CRC and other epithelial cancers (such as pancreatic or lung) is that loss of Apc, and therefore activation of Wnt signaling, is very frequent, and often required for tumorigenesis. Preliminary evidence from our lab shows that, in the colon, K-RasA146T, K- RasG13D, and K-RasG12D expression manifest in distinct phenotypes, with differing levels of Ras activation. However, in the background of Apc loss, and therefore in CRC, the weaker alleles of K-Ras (G13D and A146T) are now hyper-activated, and phenotypically indistinguishable from K-RasG12D. I hypothesize that the loss of Apc, and therefore activation of Wnt signaling, serves to activate the weak alleles of K-Ras, likely by altering expression of the GTPase activating proteins (GAPs) that regulate K-Ras. I propose to test this hypothesis in mouse colon organoids, using established methods to externally modulate Wnt levels, and to see how this affects K-Ras activation in the context of the various mutant alleles. Additionally, using existing conditional mouse models for these K-Ras mutant alleles, I will characterize their phenotypic and molecular properties in the pancreas, and determine if the absence of Wnt signaling in this tissue serves to enrich a certain subset of mutations. The findings generated in this study will help establish the importance of tissue-specific genetic interactions of K-Ras – an area of study important to use precision medicine to design therapeutic strategies targeting K-Ras mutant cancers.