20.06.23 Ewing sarcoma breakpoint region 1

Question 1

How common is Ewing Sarcoma

Answer 1

-2nd most common bone tumour of childhood and adolescence that can also arise in soft tissue

Question 2

Mean age of diagnosis of Ewing Sarcoma

Answer 2

~15 years

Question 3

What is the survival rate of Ewing Sarcoma

Answer 3

-70-80% unless it’s metastatic then 30%.

Question 4

What is the histology of Ewing Sarcomas

Answer 4

-Small round cells expressing high levels of CD99

Question 5

What gene families are involved in EWS translocations

Answer 5

• FET gene family (FUS, EWSR1, TAF15)

- ETS transcription factor (FLI1, ERG)

Question 6

What is the common translocation seen in Ewing Sarcoma

Answer 6

• t(11;22)(q24;q12)
• EWSR1-FLI1
• Seen in 85-90% cases
• N terminal transcriptional activation domain of EWSR1 gene is fused to carboxy-terminus DNA binding domain of transcription factor FLI1
• Acts as an aberrant TF
• Reciprocal FLI1-EWS fusion is not expressed

Question 7

Other alternative fusions act in a similar manner

Answer 7

• Amino terminal transcriptional domain of EWSR1 and a DNA binding domain of a transcription factor and result in aberrant TFs.
• EWSR1 -ERG (10-15% cases)
• EWSR1 -FEV/ETV1/ETV4 (<1%)

or non ETS oncogenes:

• EWSR1 -NFATC2
• EWSR1 -POU5F1

Question 8

Disease mechanism of EWS-FLI fusions

Answer 8

• Abberant transcriptional activation and repression.
• EZH2 is a transcriptional target of fusion gene. EZH2 represses gene expression by histone methylation.
• NKX2.2 another target, represses transcription by recruiting transcriptional corepressors and HDACs to gene promoters.
• Fusion gene may be involved in RNA splicing.
• EWSR1 is involved in transcriptional response to DNA damage by promoting homologous recombination.

Question 9

Origin of EWS-FLI fusions

Answer 9

• Analysis of interchromosomal junctions of t(11;22) translocation does not rely on site-specific recombination nor regions of homology.
• Predicted to arise through illegitimate recombination

Question 10

Treatment of Ewings sarcoma

Answer 10

-Surgical resection, local radiotherapy, multi agent chemotherapy.

Question 11

Monitoring of disease

Answer 11

-Liquid biopsies are beneficial as tumours are often in difficult to approach sites for biopsy.

Question 12

Uses of genetic testing

Answer 12

• Determine type of fusion gene present
• Availability in future for targeted therapies.
• Improved understanding of disease mechanism.