Epigenetic determinants in soft tissue sarcomas: molecular mechanisms and therapeutic targets

ABSTRACT

Introduction

Soft tissue sarcomas are a group of rare, mesenchymal tumors characterized by dismal prognosis in advanced/metastatic stages. Knowledge of their molecular determinants is still rather limited. However, in recent years, epigenetic regulation – the modification of gene expression/function without DNA sequence variation – has emerged as a key player both in sarcomagenesis and sarcoma progression.

Areas covered

Herein, we describe and review the main epigenetic mechanisms involved in chromatin remodeling and their role as disease drivers in different soft tissue sarcoma histotypes, focusing on epithelioid sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. Focusing on chromatin-remodeling complexes, we provide an in-depth on the role of BAF complex alterations in these soft tissue sarcoma histotypes. In parallel, we highlight current state-of-the-art and future perspectives in the development of rational, innovative treatments leveraging on epigenetic dysregulation in soft tissue sarcomas.

Expert opinion

Therapeutic options for metastatic/advanced sarcomas are to date very limited and largely represented by cytotoxic agents, with only modest results. In the continuous attempt to find novel targets and innovative, effective drugs, epigenetic mechanisms represent an emerging and promising field of research, especially for malignant peripheral nerve sheath tumors, epithelioid and synovial sarcoma.

KEYWORDS:

• Epigenetics
• BAF
• epithelioid sarcoma
• synovial sarcoma
• soft tissue sarcoma

Article highlights

• Soft tissue sarcomas are rare mesenchymal tumors with dismal prognosis in advanced stages.

• Epigenetics has recently emerged as a key player in selected soft tissue sarcoma histotypes, such as malignant peripheral nerve sheath tumor, epithelioid sarcoma and synovial sarcoma.

• The most relevant epigenetic determinants for these soft tissue sarcoma histotypes are genes and proteins involved in chromatin remodeling, in particular, members of the Polycomb repressive complexes and members of the BAF complexes.

• Better understanding of the molecular epigenetic mechanisms driving sarcomagenesis and sarcoma progression in these histotypes is providing relevant cues for the development of innovative therapeutic strategies.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Associazione “Orchestra per la Vita” Aps (A Merlini, D Sangiolo). A Merlini research activity is supported by PON 2014-2020 1062/2021 PNR 2021-2027. L D’Ambrosio research activity is partially supported by Grant of Internationalization from the Department of Oncology of the University of Turin.