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Epigenetic Alterations in Bone and Soft Tissue Tumors
John Wojcik1, Kumarasen Cooper
1*Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania †University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Abstract:
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.
Insights
Human cancers arise from genetic and epigenetic alterations. Mutations in epigenetic regulators, like Polycomb and SWI/SNF complexes, are key drivers, especially in mesenchymal and neuroectodermal tumors.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Human malignancies stem from heritable alterations, including DNA sequence changes and epigenetic modifications affecting gene expression.
- High-throughput sequencing reveals mutations in epigenetic regulatory complexes are crucial in cancer development.
- Epigenetic regulators control chromatin accessibility and gene transcription, and their dysfunction can activate oncogenes or silence tumor suppressors.
Purpose of the Study:
- To review recent advances in understanding the molecular pathogenesis of specific human malignancies.
- To focus on tumors where alterations in Polycomb complexes, SWI/SNF remodelers, and histones are central to disease development.
- To highlight the link between molecular pathogenesis and novel diagnostic markers.
Main Methods:
- Review of recent scientific literature on epigenetic alterations in cancer.
- Analysis of high-throughput sequencing data implicating epigenetic regulators in oncogenesis.
- Focus on molecular mechanisms in mesenchymal and neuroectodermal tumors.
Main Results:
- Epigenetic regulators, particularly Polycomb and SWI/SNF complexes and histones, are frequently altered in human cancers.
- These alterations play a critical role in the pathogenesis of mesenchymal and neuroectodermal tumors.
- Understanding these molecular mechanisms facilitates the development of new diagnostic markers.
Conclusions:
- Epigenetic dysregulation is a fundamental mechanism in human tumorigenesis.
- Targeting epigenetic pathways presents potential therapeutic strategies.
- Advances in molecular pathology are improving cancer diagnosis and classification.
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