*Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania †University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Adv Anat Pathol. 2017 Nov;24(6):362-371. doi: 10.1097/PAP.0000000000000167.
Human malignancies are driven by heritable alterations that lead to unchecked cellular proliferation, invasive growth and distant spread. Heritable changes can arise from changes in DNA sequence, or, alternatively, through altered gene expression rooted in epigenetic mechanisms. In recent years, high-throughput sequencing of tumor genomes has revealed a central role for mutations in epigenetic regulatory complexes in oncogenic processes. Through interactions with or direct modifications of chromatin, these proteins help control the accessibility of genes, and thus the transcriptional profile of a cell. Dysfunction in these proteins can lead to activation of oncogenic pathways or silencing of tumor suppressors. Although epigenetic regulators are altered across a broad spectrum of human malignancies, they play a particularly central role in tumors of mesenchymal and neuroectodermal origin. This review will focus on recent advances in the understanding of the molecular pathogenesis of a subset of tumors in which alterations in the polycomb family of chromatin modifying complexes, the SWI/SNF family of nucleosome remodelers, and histones play a central role in disease pathogenesis. Although this review will focus predominantly on the molecular mechanisms underlying these tumors, each section will also highlight areas in which an understanding of the molecular pathogenesis of these diseases has led to the adoption of novel immunohistochemical and molecular markers.
人类恶性肿瘤是由导致不受控制的细胞增殖、侵袭性生长和远处转移的遗传改变驱动的。遗传变化可以来自 DNA 序列的改变，或者通过根植于表观遗传机制的基因表达改变。近年来，肿瘤基因组的高通量测序揭示了表观遗传调控复合物中的突变在致癌过程中的核心作用。这些蛋白质通过与染色质的相互作用或直接修饰，帮助控制基因的可及性，从而控制细胞的转录谱。这些蛋白质的功能障碍可导致致癌途径的激活或肿瘤抑制因子的沉默。尽管表观遗传调节剂在广泛的人类恶性肿瘤中发生改变，但它们在间充质和神经外胚层来源的肿瘤中起着特别核心的作用。这篇综述将重点介绍近年来对一组肿瘤的分子发病机制的理解的最新进展，其中染色质修饰复合物多梳家族、核小体重塑 SWI/SNF 家族和组蛋白的改变在疾病发病机制中起着核心作用。尽管这篇综述将主要侧重于这些肿瘤的分子机制，但每一节还将强调在这些疾病的分子发病机制的理解导致采用新的免疫组织化学和分子标志物的领域。
