14 Questions
What is the consequence of a translocation on the gene preceding the breakpoint?
The gene loses a part of its own protein
Which of the following techniques is NOT suitable for detecting translocations in decalcified tissue?
FISH
What is the main advantage of using next-generation sequencing (NGS) for translocation detection?
It provides information on the fusion partner
What is the primary function of the EWSR1-FLI1 fusion protein in Ewing sarcoma?
Stimulating cell proliferation
Which of the following is a target gene of the EWSR1-ETS fusion protein?
PDGF-C
What is the approximate 5-year survival rate for patients with Ewing sarcoma?
60-65%
What is the first step in analyzing the biopsy of the 8-year-old boy with a large tumor in the bone marrow?
Cut sections with the microtome and stain with H&E
What is the characteristic of a chimeric gene?
A gene with a swapped promoter and coding region
What is the primary function of a promoter in a gene?
To regulate the expression of the gene
What is the purpose of immunohistochemistry in diagnosing small blue round cell tumors?
To define the line of differentiation using markers
What is the characteristic of osteosarcoma in terms of its karyotype?
It has a complex karyotype
What is the purpose of molecular testing in diagnosing small blue round cell tumors?
To identify the specific genetic alteration in the tumor DNA
What is the result of a promoter swap in a gene?
The gene is highly expressed, causing dysregulation
What is the characteristic of Ewing sarcoma in terms of its genetic alteration?
It has a specific translocation
Study Notes
Ewing Sarcoma and Molecular Diagnostics
- Ewing sarcoma is characterized by a specific translocation.
Sarcoma Genesis
- Chondrosarcoma is associated with a specific mutation and follows a multistep model.
- Osteosarcoma has a complex karyotype.
Age-Specific Incidence of Bone Sarcomas
- The incidence of bone sarcomas varies with age.
Case 1 Diagnosis
- The patient's biopsy shows a large tumor filling the bone marrow with a "small blue round cell" appearance.
- Differential diagnoses include Ewing sarcoma, Rhabdomyosarcoma, Neuroblastoma, Non-Hodgkin lymphoma/leukemia, Small cell osteosarcoma, Mesenchymal chondrosarcoma, and Poorly differentiated monophasic synovial sarcoma.
- Immunohistochemistry (IHC) and histochemical staining are used to narrow down the diagnosis.
- IHC profiles may overlap, requiring molecular testing for specific genetic alterations.
- Molecular testing reveals a specific translocation, which is an early step in tumorigenesis.
- The fusion product is essential in tumor formation, leading to dysregulation and cancer.
Translocation Detection Techniques
- Techniques for translocation detection include:
- Conventional cytogenetics (fresh tissue)
- RT-PCR (frozen tissue, paraffin)
- FISH (paraffin material, not decalcified)
- Immunohistochemistry
Next-Generation Sequencing (NGS)
- NGS can detect the fusion partner and is used for translocation detection.
- In Case 1, NGS analysis using Archer reveals an EWSR1-FLI1 fusion, diagnostic of Ewing sarcoma.
Treatment and Prognosis
- Treatment options for Ewing sarcoma include resection, chemotherapy, and radiation.
- The 5-year survival rate is approximately 60-65%.
EWSR1-ETS Target Genes
- The EWSR1-FLI1 fusion protein orchestrates a list of target genes involved in:
- Stimulation of cell proliferation (upregulation of PDGF-C, CCDN1, c-Myc)
- Evading growth inhibition (downregulation of cyclin-dependent kinase inhibitors, TGF beta type II receptor)
- Escape from senescence (upregulation of hTERT, increased telomerase activity)
- Escape from apoptosis (repression of IGFBP-3 promoter)
- Angiogenesis (VEGF expression)
- Invasion and metastases (MMP?)
This quiz covers the diagnosis and molecular characteristics of bone sarcomas, including Ewing sarcoma, chondrosarcoma, and osteosarcoma. It also discusses age-specific incidence and case studies
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