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Clinical update · 01 of 06

MTAP immunohistochemistry resolves ambiguous deletion calls from exome sequencing

When sequencing gives an indeterminate MTAP call, run MTAP IHC; it reclassified many heterozygous calls as true homozygous deletions.

Pathology·25 September 2026 ·1 min read
Design
Pan-cancer concordance study, NGS vs IHC with FISH and RNA-seq validation
Population
2409 tumours with whole-exome sequencing (EXOMA2), IHC subset
Primary outcome
Concordance of MTAP IHC with genomic classification
Effect
High concordance for wild-type and homozygous deletion; IHC reclassified a substantial share of heterozygous calls as homozygous loss

MTAP deletion, usually alongside CDKN2A loss, is becoming a therapeutic biomarker because MTAP-deficient tumours are vulnerable to PRMT5 and MAT2A inhibitors now in trials. Sequencing detects it, but copy-number calls can be indeterminate.

This study took 2409 tumours from the EXOMA2 whole-exome programme and classified MTAP as wild-type, homozygously deleted or probably heterozygously deleted. A subset was tested with three MTAP antibody clones, with FISH and RNA sequencing in selected cases. IHC agreed closely with NGS for wild-type and homozygous deletion. For heterozygous calls, IHC showed loss of protein in a substantial proportion, and FISH confirmed homozygous deletion in these. The ambiguous calls were not driven by low tumour cellularity.

For laboratories, the message is that a heterozygous or borderline MTAP call on NGS should not be taken at face value. IHC is cheap, quick and widely available, and should be the next step, with FISH where IHC is equivocal.

  • Treat a heterozygous or borderline MTAP call on sequencing as unresolved
  • Use MTAP IHC to clarify it; loss of expression suggested homozygous deletion confirmed by FISH
  • Do not assume an ambiguous call reflects low tumour content; cellularity did not explain it here
  • Report MTAP status explicitly where patients may be eligible for PRMT5 or MAT2A inhibitor trials
  • Validate the chosen MTAP clone locally before diagnostic use

Why it matters

MTAP status may soon decide eligibility for a new drug class, so equivocal NGS reports will have consequences.

Don't overread it

PRMT5 and MAT2A inhibitors are still investigational; MTAP status does not yet select an approved treatment.

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