Gastrointestinal Stromal Tumour
Gastrointestinal stromal tumour is the most common mesenchymal tumour of the gastrointestinal tract, and one of the clearest examples in oncology of a disease reorganised by identifying its driver alteration. The specific alteration, not merely the gene, governs the discussion.
Disease categories
Major disease categories
- KIT-mutant GIST
- PDGFRA-mutant GIST
- SDH-deficient GIST
- NF1-associated GIST
- Wild-type GIST
Molecular
Molecular considerations
KIT alterations, most often in exon 11, are the most frequent driver. PDGFRA alterations, including the D842V variant which behaves differently from other PDGFRA alterations, account for a further group. Tumours without KIT or PDGFRA alterations are assessed for SDH deficiency and NF1 association.
Markers commonly discussed in gastrointestinal stromal tumour
- KIT (exon 11, 9 and others)
- PDGFRA (including D842V)
- SDHB immunohistochemistry
- NF1
- DOG1
- Mitotic index
Not exhaustive, and not every marker is assessed in every patient. Which of these is relevant depends on the individual case and should be discussed with the treating team.
Testing
Genomic testing considerations
Mutational testing is a standard part of the discussion, and recording the specific exon and variant matters because different alterations behave differently.
Germline
Germline considerations
Germline assessment is discussed in SDH-deficient disease, in paediatric presentations, and where there is a family history or multifocal tumours.
Molecular monitoring
ctDNA and liquid biopsy considerations
ctDNA is used in research and practice discussion to detect secondary resistance alterations, which are frequently heterogeneous between lesions.
Single-cell & computation
Single-cell and algorithmic approaches
Single-cell analysis in sarcoma is used to characterise differentiation state and the stromal and immune compartments, both of which vary widely across a group of more than a hundred entities. Single-cell DNA sequencing contributes to clonal structure questions in tumours that are frequently heterogeneous. Algorithm work centres on fusion detection and breakpoint characterisation — the defining event in many sarcoma subtypes — together with methylation-based classification for diagnostically difficult cases.
Decisions
Treatment decision questions
Questions worth raising with a treating team when a decision is being made:
- Is the specific KIT or PDGFRA alteration recorded, including exon?
- If neither is present, has SDH deficiency been assessed?
- Are tumour size, site and mitotic index documented for risk assessment?
Resistance
Resistance and recurrence questions
- Has a secondary resistance alteration been sought at progression?
- Is progression occurring at one site or several, since resistance is often heterogeneous?
Trials
Clinical trial considerations
The specific driver alteration and prior therapy lines largely determine eligibility.
When a precision oncology review may help
A review is most useful where the standard pathway has been exhausted or where the picture is more complicated than a protocol accounts for — rare presentations, treatment resistance, complex or apparently contradictory molecular findings, or a decision between several defensible options.
The output is a structured analysis and a set of questions for the treating team. It is not treatment, and it does not replace the treating oncologist.