Key Points
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Human sarcomas are uncommon malignancies that arise from mesenchymal cell types, have varied genetic origins and are clinically heterogeneous. Many sarcomas arise de novo, driven by a single genetic abnormality, and some are progressive and harbour complex genomes.
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Three core and context-dependent molecular mechanisms drive sarcomagenesis: dysregulation of gene expression by aberrant, chimeric transcription factors generated by specific gene fusions in translocation-associated sarcomas, somatic mutations affecting key signalling pathways and DNA copy-number abnormalities.
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Novel genomic findings from diverse approaches in sarcoma are identifying point mutations that co-occur with translocations, lineage-specific oncogenes, chromosome remodelling events, and both genomic alterations and mutations that alter canonical signalling and differentiation pathways.
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As integrative genomics and massively parallel sequencing increase the pace of discovery for the most common lesions in all but the rarest sarcomas, this necessitates renewed focus on developing in vitro and in vivo sarcoma models for accompanying target discovery and functional annotation of sarcoma genomes with genomics-guided functional genetics.
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Although conventional modalities predominate in sarcoma treatment, new approaches to target aberrant signalling with specific therapies, overcome acquired resistance and target unconventional pathways are rapidly evolving.
Abstract
Increasingly, human mesenchymal malignancies are being classified by the abnormalities that drive their pathogenesis. Although many of these aberrations are highly prevalent within particular sarcoma subtypes, few are currently targeted therapeutically. Indeed, most subtypes of sarcoma are still treated with traditional therapeutic modalities, and in many cases sarcomas are resistant to adjuvant therapies. In this Review, we discuss the core molecular determinants of sarcomagenesis and emphasize the emerging genomic and functional genetic approaches that, coupled with novel therapeutic strategies, have the potential to transform the care of patients with sarcoma.
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Change history
22 July 2011
In Table 2 of this article, there were errors in two of the cells. In the Sunitinib row, under the 'Tumour types' heading, "GIST" should have read "Imatinib-resistant GIST". Also in the Sunitinib row, under the 'Approximate response rate' heading, "80%" should have read "8%". This has now been corrected online.
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Acknowledgements
The authors apologize to the many authors whose relevant work they were unable to cite here owing to space limitations. They thank N. Schultz for providing pathway expertise, C.D.M. Fletcher for critical reading, and M. Meyerson and C. Sander for advice and support. This work was supported in part by The Soft Tissue Sarcoma Program Project (P01 CA047179 to S.S., M.L. and C.R.A.) and the SPORE in Soft Tissue Sarcoma (P50 CA140146-01 to S.S., M.L., C.R.A. and B.S.T.).
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R.G.M. is a member of the advisory board of Novartis, Eisai, GlaxoSmithKline and Lilly, and has research support from Pfizer, Roche and Eisai. The other authors declare no competing financial interests.
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DATABASES
FURTHER INFORMATION
Glossary
- Translocations
-
Structural rearrangement that juxtaposes distant genome sequences, resulting in aberrant gene expression or modified regulatory control of a gene (promoter substitution) or the formation of a fusion gene that encodes an aberrant, chimeric protein (gene fusion). Pathognomonic translocations have more than diagnostic use, they are also the defining feature of the given tumour type.
- Myogenic
-
Originating in, or with expression specific to, muscular tissues.
- Karyotypically complex
-
Tumours with a complex karyotype are those with numerical and structural abnormalities affecting multiple chromosomes in the nuclear genome.
- Chromothripsis
-
A neologism coined to describe a proposed single catastrophic remodelling of a chromosome and its accompanying punctuated model of somatic cancer evolution.
- Second-generation sequencing
-
Sequencing methods and associated chemistries that sequence >106 nucleic acid fragments in parallel, producing short reads of ∼35–400 bases. Used here synonymously with next-generation or massively parallel sequencing.
- Paired-end (or mate-paired) sequencing
-
A technique whereby a library of genomic DNA or double-stranded cDNA is created and circularized, and then short stretches (35–400 bp) are sequenced from either end of the cleaved product, but not the intervening variable-length fragment (from 200–500 bp to 3–10 kb).
- RNA interference
-
A technique for sequence-specific gene silencing in which small non-coding RNAs (principally microRNAs and small interfering RNAs (siRNAs)) and associated regulatory complexes pair with complementary mRNA targets.
- Neuroectodermal
-
Of the neuroectoderm, including neural crest and neural tube cell types.
- Carney's triad
-
A rare syndrome in which there is a coexistence of three distinct tumour types: GIST, extra-adrenal paraganglioma and pulmonary chondromas.
- Carney–Stratakis syndrome
-
Distinct from Carney's triad, and also referred to as the GIST-paraganglioma dyad, a heritable syndrome in which familial mutations are associated with coexisting GIST and paraganglioma, but not pulmonary chondromas.
- Neurofibromatosis type I
-
An autosomal dominant genetic disorder in which tumours arise from nerve tissues and from all neural crest cell types.
- Paraganglioma
-
An uncommon neuroendocrine tumour arising from the sympathetic component of the autonomic nervous system and found predominantly in the abdomen, chest or head and neck region.
- Disease-specific survival
-
Patients with a given diagnosis who do not die of the specified disease in a defined period of time, which excludes patients who died from causes other than the studied disease.
- Response
-
Used here as defined by response evaluation criteria in solid tumours (RECIST) criteria. The RECIST criteria are guidelines developed to document a change in tumour burden and similarly monitor response to treatment during the clinical evaluation of cancer therapeutics.
- ORFeome
-
A collection of cloned human protein-coding open reading frames (ORFs) suitable for stable expression via destination vectors in model systems (see Further information).
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Taylor, B., Barretina, J., Maki, R. et al. Advances in sarcoma genomics and new therapeutic targets. Nat Rev Cancer 11, 541–557 (2011). https://doi.org/10.1038/nrc3087
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DOI: https://doi.org/10.1038/nrc3087
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