人类细胞拥有一套精密调控机制抑制单细胞的适合度从而保证整个生物体的适合度，但体细胞突变会打破这种限制从而激活细胞去重新寻找自己的适合度并导致癌症的发生。这种转变往往是因为一系列的DNA序列或者表观遗传的改变所引起，因此鉴别单个普通细胞转化成肿瘤细胞相关的驱动突变对于了解癌症的发生机制很有必要。申请人在研究表观遗传修饰H3K36me3缺失导致癌细胞突变率升高的基础上，拟利用MCF10A乳腺上皮普通细胞在H3K36me3缺失或H-Ras激活作用下演化成肿瘤细胞的体系建立普通细胞进化成肿瘤的体外进化模型，以此鉴定这个过程中的驱动突变并阐明其适合度，并比较两种因素下的驱动突变形式。本研究模型不仅提供一种可供选择的研究途径，避免大规模临床癌症样本测序中出现的样本不完整以及亚克隆难以鉴定等问题，而且进一步阐释了表观遗传修饰缺失在肿瘤进化中的作用，有助于更全面的了解单个普通细胞演变肿瘤的进化模式。

Human cell possess a whole set of sophisticated regulatory mechanism to suppress the fitness of single cell but ensure the fitness of whole organism, however, the somatic cell may disrupt such constraint to seek its own fitness and promote the carcinogenesis. The transformation is due to a series of DNA sequence alteration or epigenetic change, thus the identification of driver mutations for normal cell transformation is essential for understanding the mechanism of initiation of cancer. Based on the applicant’s previous study that abnormal epigenetic modification cause the elevated mutation rate in cancer cells, the applicant plan to use the normal human MCF10A mammary epithelial cells with H3K36me3 deficiency or MCF10A/H-Ras cells derived cancer evolution system to establish a in vitro model of normal cell transformation, so that we can identify the key driver mutations and clarify their fitness and compare the various driver mutation pattern under different driving force. This study not only provide an alternative research method,avoiding the incomplete sampling and difficult identification of subclone in large-scale sequencing of clinical cancer tissue, but also further elucidate the role of epigenetic modification depletion in cancer evolution, which may facilitate to comprehensively understand the evolutionary pattern of single normal cell transformation.