Sarcoma Flashcards
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)
