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Gastrointestinal Stromal Tumor With Multiple Primary Tyrosine Kinase Mutations-Clinicopathologic and Molecular
Newton A C S Wong1, Philippe Taniere2, Shaun Walsh3
1Department of Cellular Pathology, Southmead Hospital, Bristol.
Abstract:
A unique cohort of chemo-naive gastrointestinal stromal tumors (GISTs) with double-primary tyrosine kinase mutations was characterized particularly to determine whether coexistent mutations represent a single mutational event. Up to 2013, 4 UK centers reported 9 GISTs with 2 primary tyrosine kinase mutations. In each of 8 cases validated by next generation sequencing, both mutations were present in the same allele of the same exon (KIT exon 11 or 17, or PDGFRA exon 18). One case showed the second mutation only on some of the mutant alleles. Seven cases showed both mutations in all the reads, but in 2 cases, additional variants were found only in some reads. Clinicopathologic features of the 8 cases were similar to GISTs with single-primary mutations. When GIST genotyping rarely uncovers multiple tyrosine kinase variants in an exon, they occur in the same allele but are likely to represent separate mutational events and lack clinical significance.
Insights
Gastrointestinal stromal tumors (GISTs) with multiple tyrosine kinase mutations often have these alterations on the same gene allele. These coexistent mutations likely represent separate events and do not appear to impact GIST clinical features.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Gastrointestinal stromal tumors (GISTs) are rare sarcomas driven by mutations in KIT or PDGFRA genes.
- Chemo-naive GISTs with double-primary tyrosine kinase mutations present a unique challenge for understanding mutational events.
- Determining whether coexistent mutations represent a single or multiple mutational events is crucial for GIST research.
Purpose of the Study:
- To characterize a cohort of chemo-naive GISTs with double-primary tyrosine kinase mutations.
- To investigate if coexistent mutations in GISTs arise from a single mutational event.
- To assess the clinical significance of multiple tyrosine kinase variants in GIST.
Main Methods:
- Retrospective analysis of 9 GIST cases from 4 UK centers diagnosed up to 2013.
- Next-generation sequencing (NGS) validation for 8 cases to confirm mutation presence and allelic location.
- Comparison of clinicopathologic features between GISTs with single and double-primary mutations.
Main Results:
- In 8 validated cases, both primary tyrosine kinase mutations were located on the same allele within the same exon (KIT or PDGFRA).
- One case showed the second mutation on a subset of mutant alleles, while 7 cases had both mutations across all reads.
- Clinicopathologic features of GISTs with double-primary mutations were comparable to those with single-primary mutations.
Conclusions:
- Multiple tyrosine kinase variants in GIST exons, though rare, typically occur on the same allele.
- These coexistent mutations are likely the result of separate mutational events.
- The presence of multiple tyrosine kinase variants in GISTs does not appear to have clinical significance.
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