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The Sarcoma Genes: Ewing's Sarcoma

Ewing Sarcoma Family is a group of neoplasms with source on neuroectodermal primitive cells that have the potential to differentiate into various types of tumors including the Ewing sarcoma (ES), primitive neuroectodermal tumor (PNET), peripheral neuroepithelioma and Askin tumor. These three are very closely related and the main difference among them being the degree of cell dissemination. Ewing Sarcoma is the second most common bone tumor which can be seen in childhood and adolescence but can also be a soft tissue sarcoma. The bone tumor is usually seen in the pelvis or femur whereas the soft tissue Ewing Sarcoma is often seen in the buttock, thigh, and chest wall.

The symptoms of Ewing sarcoma include swelling or tenderness in the affected region, bone pain (especially night pain), unexplained weight loss and tiredness, persistent low fever. In children it is usually mistaken for sports injuries.


Genetics:

Genetically, it is mainly characterized by the presence of the fusion gene EWSR1/FLI1 or fusion of FET and ETS family members which are less common.

The members of FET and ETS family members are - EWSR1, FLI1, ERG, ETV1, ETV4, FEV, FUS.

EWSR1 - Ewing Sarcoma breakpoint region 1 located in the region 22q12.2

FLI1 - Friend leukemia integration 1 located in the region 11q24.3

ERG - v-ets erythroblastosis virus E26 oncogene like (avian) located in the region 21q22.3

ETV1 - ETS variant 1 located in the region 7p21.2

ETV4 - ETS variant 4 located in the region 17q21.31

FEV - Fifth Ewing Variant located in the region 2q35

FUS - Fused in Sarcoma located in the region 16p11.2











STAG2, TP53, EZH2 gene mutations and deletions in CDKN2A are seen in subsets of Ewing tumors. Additionally,

Ewing Sarcoma is linked with very rare germline mutations in cancer predisposition genes, especially in TP53, RET and PMS2.


Changes in terms of chromosomal numbers occurs at a particular frequency in case of Ewing Sarcoma:

Chromosomal gains - +8 is seen in around 45% of the cases.

Trisomies in chromosome number 2, 5, 7, 9, 12 are seen in around 10-15% of the cases.

Trisomy in chromosome 1q is seen in about 25% of the cases because of unbalanced translocation between 1q and 16q.


Various diagnostic tools and biomarkers available for detection of Ewing Sarcoma:

● FISH can be used as a diagnostic tool which identifies the translocations.

● Comprehensive serial profiling of tumors by targeted and whole exome sequencing of exome or cell free DNA from blood samples can be done

● Liquid biopsies can help in making therapeutic decisions from the patient’s risk profile.

● Circulating tumor cells are detected by the RT-PCR of EWSR1- FLI1 or EWSR1-ERG which links with the worst outcomes.

● CD99+ cells (Biomarker for Ewing Sarcoma) can be detected by flow cytometry in peripheral blood.

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The Sarcoma Genes: Ewing's Sarcoma

Ewing Sarcoma Family is a group of neoplasms with source on neuroectodermal primitive cells that have the potential to differentiate into various types of tumors including the Ewing sarcoma (ES), primitive neuroectodermal tumor (PNET), peripheral neuroepithelioma and Askin tumor. These three are very closely related and the main difference among them being the degree of cell dissemination. Ewing Sarcoma is the second most common bone tumor which can be seen in childhood and adolescence but can also be a soft tissue sarcoma. The bone tumor is usually seen in the pelvis or femur whereas the soft tissue Ewing Sarcoma is often seen in the buttock, thigh, and chest wall.

The symptoms of Ewing sarcoma include swelling or tenderness in the affected region, bone pain (especially night pain), unexplained weight loss and tiredness, persistent low fever. In children it is usually mistaken for sports injuries.


Genetics:

Genetically, it is mainly characterized by the presence of the fusion gene EWSR1/FLI1 or fusion of FET and ETS family members which are less common.

The members of FET and ETS family members are - EWSR1, FLI1, ERG, ETV1, ETV4, FEV, FUS.

EWSR1 - Ewing Sarcoma breakpoint region 1 located in the region 22q12.2

FLI1 - Friend leukemia integration 1 located in the region 11q24.3

ERG - v-ets erythroblastosis virus E26 oncogene like (avian) located in the region 21q22.3

ETV1 - ETS variant 1 located in the region 7p21.2

ETV4 - ETS variant 4 located in the region 17q21.31

FEV - Fifth Ewing Variant located in the region 2q35

FUS - Fused in Sarcoma located in the region 16p11.2











STAG2, TP53, EZH2 gene mutations and deletions in CDKN2A are seen in subsets of Ewing tumors. Additionally,

Ewing Sarcoma is linked with very rare germline mutations in cancer predisposition genes, especially in TP53, RET and PMS2.


Changes in terms of chromosomal numbers occurs at a particular frequency in case of Ewing Sarcoma:

Chromosomal gains - +8 is seen in around 45% of the cases.

Trisomies in chromosome number 2, 5, 7, 9, 12 are seen in around 10-15% of the cases.

Trisomy in chromosome 1q is seen in about 25% of the cases because of unbalanced translocation between 1q and 16q.


Various diagnostic tools and biomarkers available for detection of Ewing Sarcoma:

● FISH can be used as a diagnostic tool which identifies the translocations.

● Comprehensive serial profiling of tumors by targeted and whole exome sequencing of exome or cell free DNA from blood samples can be done

● Liquid biopsies can help in making therapeutic decisions from the patient’s risk profile.

● Circulating tumor cells are detected by the RT-PCR of EWSR1- FLI1 or EWSR1-ERG which links with the worst outcomes.

● CD99+ cells (Biomarker for Ewing Sarcoma) can be detected by flow cytometry in peripheral blood.

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