MTAP immunohistochemistry settled ambiguous sequencing calls across 2,409 tumours

Design

Pan-cancer concordance study within a prospective sequencing programme

Population

2,409 tumours with whole-exome sequencing; subset with IHC, FISH and RNA sequencing

Primary outcome

Agreement between MTAP IHC and sequencing-based copy number status

Effect

High concordance for wild-type and homozygous deletion; many heterozygous calls reclassified as homozygous loss by IHC and FISH

Loss of MTAP, usually through co-deletion with CDKN2A, is emerging as a biomarker for targeted drugs that act on the PRMT5-MAT2A pathway. In the EXOMA2 study (Modern Pathology, 23 September 2026), 2,409 tumours across cancer types were profiled by whole-exome sequencing and classified as MTAP wild-type, homozygous deletion or probable heterozygous deletion.

A subset with tissue was stained with three MTAP antibody clones (MTAP-RBT, 2G4 and 1813), and selected cases had FISH and RNA sequencing. Immunohistochemistry agreed closely with sequencing for wild-type and homozygous deletion. It also reclassified a substantial share of the 'probable heterozygous' calls: loss of protein in these tumours corresponded to homozygous deletion on FISH. The ambiguous sequencing calls were not explained by low tumour cellularity.

For laboratories asked to identify MTAP-deficient tumours, this supports immunohistochemistry as the first-line or arbitrating test, with FISH for confirmation where needed. It is cheaper and faster than repeat sequencing and gives a direct readout of protein loss.

• Consider MTAP immunohistochemistry when sequencing reports a borderline or probable heterozygous MTAP deletion.
• Use FISH to confirm homozygous deletion where protein loss on immunohistochemistry is unexpected.
• Do not attribute an indeterminate sequencing call to low tumour purity without checking.
• Validate your chosen MTAP clone locally, including an internal positive control in stroma.
• Report MTAP status clearly when requested for trial eligibility.

Why it matters

As MTAP becomes a treatment-selecting biomarker, a heterozygous call that is really homozygous loss could exclude a patient from therapy.

Don't overread it

The study establishes test concordance, not that MTAP-directed treatment improves outcomes.

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