Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland, New Zealand.
Department of Pathology, Dunedin School of Medicine, University of Otago, 270 Great King Street, Dunedin 9054, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Level 2, 3A Symonds Street, Auckland, New Zealand.
Semin Cancer Biol. 2018 Aug;51:149-159. doi: 10.1016/j.semcancer.2017.08.004. Epub 2017 Aug 12.
Since the completion of the first human genome sequence and the advent of next generation sequencing technologies, remarkable progress has been made in understanding the genetic basis of cancer. These studies have mainly defined genetic changes as either causal, providing a selective advantage to the cancer cell (a driver mutation) or consequential with no selective advantage (not directly causal, a passenger mutation). A vast unresolved question is how a primary cancer cell becomes metastatic and what are the molecular events that underpin this process. However, extensive sequencing efforts indicate that mutation may not be a causal factor for primary to metastatic transition. On the other hand, epigenetic changes are dynamic in nature and therefore potentially play an important role in determining metastatic phenotypes and this area of research is just starting to be appreciated. Unlike genetic studies, current limitations in studying epigenetic events in cancer metastasis include a lack of conceptual understanding and an analytical framework for identifying putative driver and passenger epigenetic changes. In this review, we discuss the key concepts involved in understanding the role of epigenetic alterations in the metastatic cascade. We particularly focus on driver epigenetic events, and we describe analytical approaches and biological frameworks for distinguishing between "epi-driver" and "epi-passenger" events in metastasis. Finally, we suggest potential directions for future research in this important area of cancer research.
自人类基因组序列的首次完成和下一代测序技术的出现以来，人们在理解癌症的遗传基础方面取得了显著进展。这些研究主要将遗传变化定义为要么是具有选择优势的癌症细胞（驱动突变），要么是没有选择优势的（不直接因果关系，乘客突变）。一个尚未解决的大问题是，原发性癌细胞如何变成转移性的，以及支持这一过程的分子事件是什么。然而，广泛的测序工作表明，突变可能不是原发性到转移性转变的因果因素。另一方面，表观遗传变化本质上是动态的，因此在决定转移表型方面可能发挥着重要作用，而这一研究领域才刚刚开始受到重视。与遗传研究不同，目前在研究癌症转移中的表观遗传事件时存在一些局限性，包括对概念的理解不足，以及用于识别潜在驱动和乘客表观遗传变化的分析框架。在这篇综述中，我们讨论了理解表观遗传改变在转移级联中作用的关键概念。我们特别关注驱动性表观遗传事件，并描述了用于区分转移中的“表观遗传驱动”和“表观遗传乘客”事件的分析方法和生物学框架。最后，我们为这一癌症研究重要领域的未来研究提出了一些可能的方向。
