Genome sequencing reveals complexity of sarcoma ‘waste paper basket’

Undifferentiated sarcoma

Pleomorphic undifferentiated sarcoma -Nephron [CC BY-SA 3.0]

Researchers have unpicked the complexity of an unusual group of rare tumours, a subset of which might be candidates for treatment with a type of cancer immunotherapy.

Undifferentiated sarcomas are a diverse group of soft-tissue tumours that cannot be accurately classified. The prognosis of this ‘wastepaper basket’ of tumours is generally poor; the median survival for patients with metastatic disease is about 12 months.

Because of their rarity and diverse nature, undifferentiated sarcomas have been little studied. However, classical chromosomal studies suggest that they are highly complex.

To gain a clearer picture, a team of scientists at UCL, the Crick and the Wellcome Sanger Institute analysed a unique series of undifferentiated sarcoma samples, donated by patients at the Royal National Orthopaedic Hospital as part of the London Sarcoma Service.

The team used a range of methods, including whole genome sequencing, to analyse 76 tumours, revealing that tumours could be classified into different groups based on the nature of their genetic abnormalities. 

Their findings, published in Cancer Cell, show that in around 15% of the tumours analysed, simple point mutations – where a single letter of the genetic code (ATCG) is changed, added or deleted – were the most commonly observed genetic changes. Several of these changes were in genes affecting the immune response to tumours, and the prognosis of patients with this type of tumour was much better than that of other patients.

The authors suggest that patients found to carry this type of mutation pattern might benefit from anticancer drugs targeting the immune system, such as checkpoint inhibitors, which work by blocking proteins that stop the immune system from attacking cancer cells.

To our amazement, we found that the sarcomas evolved over wildly different time frames, with some genetic events occurring decades before the cancers were detected. 
Peter Van Loo, Group Leader

By developing a new method to characterise the tumours’ genomic abnormalities, the team could study the evolutionary history of the cancers and work out the relative order in which genetic mutations occurred.

“To our amazement, we found that the sarcomas evolved over wildly different time frames, with some genetic events occurring decades before the cancers were detected,” says Peter Van Loo, Group Leader at the Crick and co-author of the study.

“If we could work out a way to detect these early mutations in the blood, then it’s possible we could intervene before the cancer became aggressive years later.”

The nature of these genomic changes has provided insight into how these complex patterns of mutations lead to undifferentiated sarcomas. Additionally, the new tools developed to analyse the evolutionary history of the tumour samples can now be applied to the analysis of other genomically complex cancer types.

Nischalan Pillay, lead author from the UCL Cancer Institute, said: “In the coming months, NHS patients will have the option of having their cancers whole genome sequenced. Our findings illustrate why this will be valuable, as we would be able to identify undifferentiated sarcoma and other cancer patients suitable for clinical trials of immune checkpoint inhibitors.”

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