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Mechanisms of sarcoma development

Key Points

  • Sarcomas are a diverse group of relatively rare malignancies that are derived from bone, muscle, cartilage and other connective tissues.

  • Genetically, sarcomas fall into two main categories. One group of sarcomas is characterized by a tumour-specific translocation that seems to be central to the pathogenesis of the tumour, and indeed is being incorporated as diagnostic criteria. Another group of sarcomas are characterized not by a recurring, tumour-specific genetic alteration but by complex karyotypes that are characteristic of severe genetic and chromosomal instability.

  • Most sarcomas have abnormalities in the RB, p53 and/or specific growth-factor signalling pathways. In several specific sarcoma types, specific genetic alterations lead to activation of specific tyrosine kinase growth-factor receptors, and these have been successfully treated with drugs that specifically inhibit the activated kinase receptor.

  • Therapeutic interventions that are aimed at inhibiting these activated pathways have already shown activity in the treatment of specific sarcomas. It is likely that further evolution of the classification of these tumours based on biological properties, in addition to histological classifications, will allow for more specific therapeutic interventions.

  • It has been relatively difficult to develop genetic animal models of translocation-specific sarcomas, and work is ongoing to do so. There are several mouse models of sarcomas that do not harbour tumour-specific translocations.

  • In the future, therapy for sarcomas is likely to involve use of agents that specifically target activated growth-factor signalling pathways — often in combination with standard cytoreductive chemotherapy and surgery. It is likely that this approach will convert an acute, often lethal disease to a chronic, non-debilitating one.


Sarcomas are a rare and diverse group of tumours that are derived from connective tissues, including bone, muscle and cartilage. Although there are instances of hereditary predisposition to sarcomas, the overwhelming majority of such tumours are sporadic. In the past decade, we have gained much insight into the genetic abnormalities that seem to underlie the pathogenesis of these tumours. This information has already led to new classification of many sarcomas, as well as to successful therapies that are targeted at specific genetic abnormalities. It is likely that this approach will lead to continued refinements in classification and treatment of these tumours.

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Figure 1: Spectral karyotyping of sarcoma.
Figure 2: Defects in the p53 and RB pathways in sarcomas.
Figure 3: Sarcoma defects in growth-factor signalling pathways.


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bone sarcoma

Ewing's sarcoma


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hereditary retinoblastoma

Li–Fraumeni syndrome

neurofibromatosis type I

dermatofibrosarcoma protuberans


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Microarray web sites

Sarcoma web site



(Spectral karyotyping). A fluorescent in situ hybridization technique that assigns each chromosome to a unique colour.


Regions of proteins that bind to the lipid products of PI3K.


The main lipid storage tissue, as distinguished from brown fat, which functions in thermoregulation.

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Helman, L., Meltzer, P. Mechanisms of sarcoma development. Nat Rev Cancer 3, 685–694 (2003).

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