Sarcoma Flashcards
(29 cards)
What is the incidence and age of diagnosis for GIST?
Incidence - 10-15 cased per million (<1%)
Median age of diagnosis - 66-69yrs
From which type of cell does GIST arise and where in the body does it occur?
Cell - Interstitial cells of cajal
Arrises from any part of the gastrointestinal tract, most commonly the stomach (55%)
What proportions of GIST have a KIT mutation and in which exons do these typically occur (primary and secondary)?
80% of GIST cases have a KIT mutation
In the primary they typically occur in exon 11 or exon 9
Secondary mutations typically occur in exons 17 or 13
What is the prognostic significance of in frame deletions in Exon 11 of KIT in GIST and in which codons do they typically occur?
Exon 11 in frame KIT mutations are associated with a worse prognosis and typically involve the 557 or 558 codon.
What proportion of GIST cases have a PDGFRA mutation and in which exon do they typically occur?
10% of cases have a PDGFRA mutation which typically occurs in exon 18
What is the most common PDGFRA variant identified in GIST and what are the treatment implications?
The most common PDGFRA variant is the exon 18 D842V mutation which is associated with resistance to TKI treatment with imatinib, sunitinib and regorafenib. There is some indication patients may respond to dasatinib.
What genetic alterations are typically seen in the 10-15% of GISTs which are wild type for KIT and PDGFRA?
Associated with genetic alterations in RAS-MAPK pathway (gain of function RAS/BRAF mutations or loss of function NF1 mutations), succinate dehydrogenase (SDHA/B/C/D) deficiency or NTRK fusions
What germline alterations may be associated with GIST?
SDHA/B/C/A deficiency may be caused by a germline inactivating mutation in the tumour suppressor genes encoding the SDH complex (SDHA, SDHB, SDHC and SDHD subunits) or by SDHC promoter specific CpG island hypermethylation.
What is the treatment for KIT mutated GIST, primary and refractory?
Tyrosine Kinase Inhibitors:
Primary (1st line KIT exon 9/11 mut)- Imatinib
Refractory (2nd line KIT exon 13/17 mut) - Sunitinib
Refractory to Imatinib and Sunitinib - Regorafenib
What is the prevalence, age of diagnosis and prognosis for Ewing sarcoma?
Ewing sarcoma is a very rare cancer. It is commonly diagnosed un the second decade of life, however patients range from newborns to as late as the eighth decade. Prognosis is very poor as most patients harbour metastases .
How is Ewing Sarcoma diagnosed?
Initial diagnosis, treatment planning and treatment response is based on imaging. A definitive diagnosis of Ewing Sarcoma is made following tissue biopsy and histology, immunohistochemistry, molecular pathology and biobanking. Molecular pathology testing is required for a diagnosis in cases with unusual clinical or pathological features
What gene families are involved in the rearrangements characteristic of Ewing Sarcoma
The ETS (erythroblast transformation specific) family of 29 genes which play a role in cell differentiation, cell cycle control, proliferation and apoptosis.
The FET family of genes which consists of three genes FUS, EWSR1 and TAF15 are RNS binding proteins which contribute to the transcription of genes.
What is the most common ETS-FET rearrangement identified in Ewing Sarcoma and in which proportion of cases is it found?
The most frequent rearrangement is the EWSR1-FLI1 fusion t(11;22)(q24;q12) and is found in 90% of Ewing Sarcoma cases
What are the most common secondary abnormalities in Ewing Sarcoma?
Gain of chromosomes 8 and 12, gain of 1q and loss of 16q and 9q.
What is FISH used for in the diagnosis of Ewing Sarcoma and what are its limitations?
FISH break apart probes are used to detect EWSR1 rearrangements. When positive, this can only be considered consistent with a diagnosis of Ewing Sarcoma, as other sarcoma types feature EWSR1 fusions (including Ewing like). As EWSR1 FISH will only detect rearrangements involving EWSR1, it will miss fusions which involve the other FET family genes (FUS and TAF15)
What are the benefits of using NGS for a definitive diagnosis in ?Ewing Sarcoma cases?
NGS can detect all possible gene fusions between the FET family and the ETS family and identify the specific fusion partners.
NGS can also be used to distinguish Ewing like sarcomas from Ewing Sarcoma through detection of further rearrangements typically seen in Ewing like sarcoma.
RT-PCR can be used in the diagnosis of Ewing Sarcoma, what does it test and what are the limitations.
RNA based approached may be required with particular gene fusions (e.g. EWSR1-ERG) which can be difficult to detect by routine FISH, however primers need to be created for all fusion partners and testing fro all possible rearrangements may not be possible so it tends to be used for the most common variants only.
What is the difference between Ewing like sarcomas and Ewing sarcoma?
Ewing sarcomas typically lack the hallmark FET-ETS gene fusions but may exhibit other recurrent gene fusions/rearrangements
Rearrangements with what genes are most commonly identified in Ewing like sarcomas?
CIC and BCOR genes
Which gene rearrangement associated with Ewing like sarcoma can cause amplification of EWSR1 on FISH?
EWSR1-NFATc2 fusion
What is the prognosis of Ewing like sarcoma with CIC or BCOR rearrangements?
BCOR rearranged sarcomas show comparable outcome to Ewing’s patients, while CIC rearrange sarcomas have a relatively poorer prognosis and appear resistant to chemotherapy
What is the typical treatment for a soft tissue sarcoma?
Surgical resection is the mainstay of therapy
Radiotherapy or chemotherapy
Targeted therapy, however treatment options are not pervasive across soft tissue sarcomas and many remain in the clinical trial arena
What proportion of soft tissue sarcomas have specific rearrangements and what do the other cases feature?
30% of sarcomas have a specific rearrangement, the rest typically feature a complex karyotype
What are the commonly identified rearrangements and Alveolar Rhabdomyosarcoma and what is the prognosis?
• Around 20% of cases have a PAX7-FOXO1 t(1;13)(p36;q14) rearrangement
• Around 60% of cases have a PAX3-FOXO1 t(2;13)(q35;q14) rearrangement
• Around 20% are fusion negative
• Alveolar Rhabdomyosarcoma is a high grade neoplasms which is more aggressive and has a poorer prognosis than Embryonal rhabdomyosarcoma
