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The epigenomics of sarcoma

Abstract

Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma — all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation.

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Fig. 1: Schematic of the five levels of epigenomics that drive transcriptional programmes in sarcomas.
Fig. 2: Classical oncohistone mutations alter histone post-translational modification ‘writer’ complex activity.
Fig. 3: Genetic alterations in histone post-translational modification ‘writer’ complex components are found in various sarcoma subtypes.
Fig. 4: Mechanisms of action of SS18–SSX in synovial sarcoma.

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Acknowledgements

The authors thank P. Stirling, T. M. Underhill, M. Hirst, B. Dickson and E. Demicco for helpful discussions about some of the topics covered in this review, and A. Soshnev, M. Hirst and L. Wang for assistance in figure preparation. B.A.N is supported by the National Cancer Institute (NCI) (1K08CA245212-01) and the QuadW Foundation/American Association for Cancer Research (AACR) (19-40-37-NACE). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748, NIH/NCI P01CA196539, the Canadian Cancer Society (705615) and the Terry Fox Research Institute (1082).

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B.A.N., K.B.J., A.M.I., J.S.E.Y., W.D.T. and T.O.N. researched data for the article. B.A.N., K.B.J., A.M.I., W.D.T., M.L., C.D.A. and T.O.N. provided a substantial contribution to discussion of the content. All authors contributed to writing the article and to the review and/or editing of the manuscript before submission.

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Correspondence to Torsten O. Nielsen.

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Competing interests

A.M.I. previously consulted for Foundation Medicine, Inc. W.D.T. reports personal fees from Agios Pharmaceuticals, Eli Lilly, EMD Serono, Eisai, Janssen, Immune Design, Daiichi Sankyo, Blueprint, Loxo, GlaxoSmithKline, NanoCarrier and Deciphera outside the submitted work. In addition, W.D.T. has a patent Companion Diagnostic for CDK4 inhibitors (14/854,329 pending to Memorial Sloan Kettering Cancer Center (MSKCC)/Sloan Kettering Institute (SKI). W.D.T. is also on the scientific Advisory Board of Certis Oncology Solutions and Atropos Therapeutics (both stock ownership) and is a consultant for Daiichi Sankyo (FDA Oncologic Drugs Advisory Committee (ODAC) meeting, pexidartinib). T.O.N. has a patent on the Prosigna breast cancer diagnostic (Veracyte Technologies) outside the submitted work. B.A.N., K.B.J., J.S.E.Y., C.D.A. and M.L. declare no competing interests.

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Glossary

Undifferentiated pleomorphic sarcoma

A malignant mesenchymal tumour of undefined histogenesis, with histologically characterized high-grade spindle cells producing a non-specific collagenous matrix. Previously termed malignant fibrous histiocytoma, this sarcoma is classified as a diagnosis of exclusion.

Ewing sarcoma

A malignant bone or soft tissue tumour comprising uniform small blue round cells, typically affecting children and adolescents. Driven by chromosomal translocations resulting in transcripts fusing FET genes with genes encoding ETS family transcription factors, Ewing sarcoma breakpoint region 1 (EWSR1)–friend leukaemia virus integration 1 (FLI1) being the most common variant.

Synovial sarcoma

A malignant translocation-associated sarcoma driven by the SS18SSX gene fusion. Although frequently arising in extremities near joints, the term is a misnomer as the cell of origin is unknown and the tumour is not derived from synovium and does not differentiate into synovial-type tissue. Synovial sarcoma exists as monophasic spindle cell forms or as a biphasic type with areas of epithelial differentiation.

Gastrointestinal stromal tumours

(GISTs). Mesenchymal neoplasm of the gastrointestinal tract, derived from the interstitial cells of Cajal. Activating mutations in the KIT (or PDGFRA) receptor tyrosine kinases are the key initiating oncogenic events in the majority of cases, making imatinib and related tyrosine kinase inhibitors an effective targeted therapy for this disease.

Chondrosarcomas

Malignant cartilaginous matrix-producing tumours often driven by isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations. Typically arising in the axial skeleton of middle-aged patients, these sarcomas can be slow growing but resistant to existing systemic therapy and radiotherapy.

Nucleosomes

Basic repeating structural units of the chromosome consisting of 8 histone proteins (2 each of 4 core histones: H3, H4, H2A and H2B) with 147 base pairs of DNA wrapping the structure.

Giant cell tumour of bone

A benign but often locally aggressive neoplasm of bone in young adults driven by missense histone mutations at the histone H3.3 G34 variant. These tumours have a propensity for local recurrence and present as radiolytic lesions that destroy bone underneath articular surfaces.

Chondroblastoma

A benign cartilaginous neoplasm that characteristically arises at the ends of long bones, close to the joints, and occurs predominantly in adolescents. It is driven by the histone H3.3 K36M mutation.

Malignant peripheral nerve sheath tumours

(MPNSTs). Sarcomas arising within peripheral nerves, about half of which are sporadic and half of which occur in the context of congenital NF1 (neurofibromatosis type 1) inactivating mutations. Development of MPNSTs is additionally driven by (often mutually exclusive) loss-of-function alterations in suppressor of zeste 12 (SUZ12) or embryonic ectoderm development (EED).

Malignant rhabdoid tumours

Highly aggressive, malignant tumours that occur in infants and young children. Three presentations exist — kidney, extrarenal and brain (the latter being termed atypical teratoid/rhabdoid tumour) — and all are characterized by bi-allelic deletion of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1).

Epithelioid sarcoma

Malignant soft tissue sarcoma in distal extremities, with mixed features of mesenchymal and epithelial differentiation. It typically affects adolescents and young adults, metastasizes aggressively and is resistant to conventional chemotherapies. Epithelioid sarcoma is characterized by inactivating mutations in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1).

Chromatin remodelling complexes

Multiple families of protein complexes that alter chromatin structure (that is, histone–DNA and histone–histone contacts) to regulate gene expression in an ATP-dependent fashion. Their functions include alteration of nucleosome assembly (maturation and spacing), chromatin access (nucleosome repositioning or ejection) and nucleosome editing (histone exchange or eviction). SWI/SNF complexes are one such family of chromatin remodelling complexes.

Enhancer

A gene regulatory element that binds transcription factors and cofactors to activate transcription of target genes that may be located a relatively far linear distance away, and independent of their orientation on DNA.

Bisulfite sequencing

The current gold-standard sequencing strategy for detecting DNA methylation based on the conversion of unmethylated cytosine to uracil after treatment with sodium bisulfite (without modification of methylated cytosine). Reduced representation bisulfite sequencing is a variation on this method that selects for areas of the genome rich in CpG islands, including promoters, with less starting material required and lower cost.

CpG islands

Segments of genomic DNA, several hundred base pairs in length, that contain a large number of CpG dinucleotide (where a cytosine is followed by a guanine) repeats. When occurring near promoters of expressed genes, CpG islands are usually unmethylated; in contrast, CpG dinucleotides occurring in other contexts tend to be methylated.

Small blue round cell sarcomas

Undifferentiated mesenchymal tumours with uniform round nuclei and very little cytoplasm that are histologically difficult to distinguish, including not only Ewing family tumours but several rarer and emerging entities with distinctive molecular drivers, prognoses and responses to therapy.

Polycomb group

(PcG). A group of proteins originally discovered in Drosophila involved in the establishment and maintenance of developmental gene expression programmes through formation of polycomb repressive complexes (PRCs) that repress gene expression by methylation of histone H3 K27 (PRC2) and ubiquitylation of H2A K119 (PRC1).

DNA hydroxymethylation

A type of DNA modification in which the oxidation of methylated cytosines at CpG dinucleotides to 5-hydroxymethylcytosine is catalysed by the TET family of methylcytosine dioxygenases. This process serves as an intermediate step in DNA demethylation.

Contact inhibition

A fundamental property of normal cells to cease proliferation or migration when in contact with neighbouring cells.

Chromatin insulator

DNA elements and protein binding partners, including CCCTC-binding factor (CTCF), that protect nearby genes from adjacent chromatin regulatory domains and can limit enhancer–promoter interactions.

Endometrial stromal sarcomas

(ESSs). Uterine malignancies with low and high-grade forms that are associated with distinct genetic rearrangements and fusion oncogenes. Typically presenting in middle age, the disease is relatively slower to progress than most other types of sarcoma.

Angiosarcoma

An aggressive, malignant endothelial cell tumour of vascular or lymphatic origin that can arise anywhere in the body, sporadically or sometimes in association with radiation exposure or lymphoedema. Angiosarcomas are especially infiltrative and prone to metastatic spread.

Desmoplastic small round cell tumour

An aggressive, malignant neoplasm and member of the small blue round cell tumour family that typically presents as a large mass in the abdomen of adolescent and young males. It is characterized by a translocation resulting in Ewing sarcoma breakpoint region 1 (EWSR1)–WT1 fusion transcripts; this sarcoma does not respond well to any currently available systemic therapies.

Homologous recombination

The exchange of nucleotide sequences between two similar or identical DNA strands that is used to generate sequence variation during meiosis or to direct error-free repair of DNA double-strand breaks.

Sarcomatoid tumours

A descriptive term for neoplasms of non-mesenchymal origin that develop a sarcoma-like histological phenotype (characterized by spindle cell cytomorphology, matrix production and cell–matrix interactions); for example, carcinomas that have undergone epithelial–mesenchymal transition.

Mediastinal tumours

A term for primary neoplasms of the thoracic cavity, other than lung cancers.

Phase separation

A physical process in which a single homogeneous liquid phase spontaneously separates into two distinct phases owing to changes in the environment, such as pH, temperature, salt or protein concentration.

Microsatellite regions

Arrays of repetitive short DNA sequences, which tend to accumulate mutations owing to the risk of strand slippage during DNA replication. These mutations are normally repaired unless there is loss of function in the mismatch repair system, which leads to microsatellite instability.

Super-enhancers

Clusters of enhancers in close genomic proximity with high concentrations of bound transcriptional co-activators that control gene expression programmes to regulate cell identity.

Chromatin looping

A model for long-range control of gene expression to allow for direct contact of promoters and enhancers over long linear distances by looping out the intervening chromatin. Loops are mediated and stabilized by proteins and complexes including CCCTC-binding factor (CTCF), mediator and cohesin.

Chromatin immunoprecipitation followed by sequencing

(ChIP–seq). A technique used to identify the DNA sequences that are in close physical proximity to a chromatin-associated protein, transcription factor or other protein of interest. In this technique, the genomic DNA is fragmented and then the protein of interest is immunoprecipitated along with associated DNA fragments, which are subsequently sequenced.

Chemical degraders

Compounds that bind a target protein through one chemical domain and through a second domain recruit the cereblon E3 ubiquitin ligase complex leading to degradation of the target protein. Degradation can have a distinct biological effect from small-molecule inhibition of the target in cases where the target protein has non-enzymatic functions.

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Nacev, B.A., Jones, K.B., Intlekofer, A.M. et al. The epigenomics of sarcoma. Nat Rev Cancer 20, 608–623 (2020). https://doi.org/10.1038/s41568-020-0288-4

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