肿瘤转移过程中基因突变和表观遗传变异协同性进化的规律

Tumor metastasis is a micro-evolutionary process which has been selected by the clone competition. The coordination of genetic and epigenetic alterations drives tumor cells to evolve the fitness to the distinct new micro-environment. Recent studies show there are great variances among individual cancer patients. Cancer is a personalized disease. Previous association studies have showed that common variants implicated account for only a small proportion of the genetic component and much of the missing heritability lies within the huge class of relatively or very rare genetic variants which were not represented in the association studies. However, each cancer patient has his own driver mutations. But it is still limited understood how genetic mutations coordinate with epigenetic changes drive the tumor cells to metastasize to other organs and evolve the fitness new microenvironments. Here, we will combine genomics, cell biology and genetic methods to study the mechanism of metastasis by population evolutionary strategy. We will compare the genomic and epigenomic features among primary tumor, matched non-tumor control tissue, metastasis tumor, and non-tumor control tissue of metastasized organ. We aim to find both the genetic and epigenetic driver mutations during tumor metastasis. We will illustrate the mechanism how genetics and epigenetics coordinate during tumor metastasis, and how metastasis tumor cells fit the new environments. Our studies will guide the personalized medicine for cancer patients

肿瘤转移是基因突变筛选及克隆竞争的微进化过程，也是基因突变和表观遗传变异协同作用适应新的微环境过程。近来发现，肿瘤是个体差异非常大的疾病，每例患者肿瘤发生和转移都有其独特的驱动变异,以往寻找共有突变的研究策略不适合肿瘤个性化特点。而且，目前对基因变异和表观遗传变异如何协同驱动肿瘤细胞转移到其它器官中，且肿瘤细胞如何适应不同的微环境等核心科学问题还有很多未知领域。因此，本课题以进化遗传学的理论为指导，结合基因组学、细胞生物学和分子遗传手段，着重探索肿瘤转移的分子机理。通过对原发灶、非癌对照组织、转移灶和转移灶周围对照组织进行基因组和表观遗传组的比较分析，在每一例肿瘤患者中寻找肿瘤转移过程中关键的基因突变和表观遗传变异，分析遗传突变和表观遗传变异的协同作用，揭示肿瘤适应微环境发生转移的分子机理，为肿瘤个体化治疗提供理论指导。

肿瘤的发生和侵袭转移过程中，发生了大量的基因组变异和表观遗传变异。基因组变异对肿瘤细胞微进化的驱动作用已经得到广泛的证实。但是，肿瘤学研究的最大的未知领域之一就是大量的表观遗传变异是否在肿瘤发生和侵袭转移过程中起驱动作用。和基因组变异相比，我们对肿瘤发生过程中表观遗传变异的图谱、肿瘤内部表观基因组异质性、以及找到起驱动作用的表观遗传学变异的生物信息学分析方法都有很多未知领域。本项目以DNA甲基化表观遗传修饰为突破口，探索DNA甲基化表观遗传信息如何传递给子代、并指导胚胎发育；并探索环境等因素通过非基因组变异驱动肿瘤发生的分子机制；以及表观遗传调控失衡能否驱动肿瘤细胞演化等核心科学问题。研究取得了良好进展，主要研究结果发表于Cell、Cancer Cell和Cell Research等核心期刊。揭示表观遗传信息在胚胎发育过程中遗传规律；阐明了肿瘤发生过程中重编程规律和作用机制；深化了对表观遗传基本规律的认识和肿瘤演化模式的认识。为进一步肿瘤早诊、预测和靶向治疗提供了理论依据。