Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer
Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer
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DOI：
10.1080/15592294.2016.1277297
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发表时间：
2017-01-01
期刊：
影响因子：
3.7
通讯作者：
Robertson, Keith D.
中科院分区：
文献类型：
--
作者：
Hlady, Ryan A.;Zhou, Dan;Robertson, Keith D.
虽然肿瘤内异质性有助于疾病进展，转移和对化疗的抵抗，但它也提供了一种了解疾病演变和驱动因素的途径。表观遗传景观的缺陷与各种人类疾病的发病机制密切相关，表观遗传失调促进肿瘤发生。了解表观遗传异质性在肝细胞癌（HCC）中至关重要，表观遗传改变是常见的，早期的和致病的事件。我们利用Infinium 450K在一系列来自单个患者肝脏的再生结节中确定了全基因组DNA甲基化和拷贝数变异。生物信息学策略用于确定患者内异质性，将表观遗传变化与临床特征联系起来，并确定其与疾病发病机制的相关性。我们的数据表明，DNA甲基化和拷贝数的改变在肝癌的癌前阶段演变，并独立地将再生结节分离成不同的簇。具有高频率表观遗传变化的再生结节具有显著较低的拷贝数变异，表明单个结节具有表观遗传和遗传组分的差异富集，两者都有助于疾病进展。基于“表观遗传进展”对再生结节进行评分，较高的评分与通过Ki67染色测量的增殖增加相关。在表观遗传学上的“侵袭性”结节中观察到的早期事件富含与肝癌有关的基因。我们的研究表明，在个体患者的早期肿瘤前肝组织中存在显着的表观遗传和遗传异质性，强调了每种机制对推动肝脏疾病进展的潜在贡献，并揭示了识别肝细胞癌表观遗传驱动因素的策略。
While intratumor heterogeneity contributes to disease progression, metastasis, and resistance to chemotherapy, it also provides a route to understanding the evolution and drivers of disease. Defects in epigenetic landscapes are intimately linked to pathogenesis of a variety of human diseases, with epigenetic deregulation promoting tumorigenesis. Understanding epigenetic heterogeneity is crucial in hepatocellular carcinoma (HCC), where epigenetic alterations are frequent, early, and pathogenic events. We determined genome-wide DNA methylation and copy number variation leveraging the Infinium 450K in a series of regenerative nodules from within single patient livers. Bioinformatics strategies were used to ascertain within-patient heterogeneity, link epigenetic changes to clinical features, and determine their relevance to disease pathogenesis. Our data demonstrate that DNA methylation and copy number alterations evolve during the pre-neoplastic phase of HCC and independently segregate regenerative nodules into distinct clusters. Regenerative nodules with a high frequency of epigenetic changes have significantly lower copy number variation, suggesting that individual nodules have differential enrichment of epigenetic and genetic components, with both contributing to disease progression. Regenerative nodules were scored based on 'epigenetic progression' with higher scores associated with increased proliferation measured by Ki67 staining. Early events observed in epigenetically 'aggressive' nodules are enriched for genes involved in liver cancer. Our study demonstrates that marked epigenetic and genetic heterogeneity exists in early pre-neoplastic liver tissue within individual patients, emphasizing the potential contributions of each mechanism to driving liver disease progression, and it unveils strategies for identifying epigenetic drivers of hepatocellular carcinoma.