MTAP immunohistochemistry resolves indeterminate deletion calls from sequencing

Design

Pan-cancer concordance study: whole-exome sequencing with orthogonal IHC, FISH and RNA sequencing

Population

2,409 tumours profiled by whole-exome sequencing, subset validated by IHC

Primary outcome

Concordance of MTAP IHC with genomic deletion status and resolution of indeterminate calls

Effect

High concordance for clear calls; IHC reclassified many indeterminate 'heterozygous' calls, confirmed by FISH

MTAP deletion, usually alongside CDKN2A loss, is becoming a biomarker for PRMT5–MAT2A-axis inhibitors, so getting the call right matters. Next-generation sequencing detects MTAP copy-number change but struggles with borderline scores, often returning an indeterminate 'heterozygous' result. This pan-cancer study profiled 2,409 tumours by whole-exome sequencing and validated a subset with immunohistochemistry using three MTAP antibody clones, with FISH and RNA sequencing on selected cases.

IHC agreed closely with sequencing for clear wild-type and homozygous-deletion calls, and — the useful part — reclassified a substantial proportion of the indeterminate 'heterozygous' cases: loss of MTAP protein matched homozygous deletion confirmed by FISH. The ambiguity was not simply a low-tumour-purity artefact.

For the reporting pathologist, this makes MTAP IHC a fast, inexpensive tiebreaker when sequencing is equivocal, rather than reflexively repeating or dismissing the molecular test. Protein loss, confirmed by FISH where needed, identifies the MTAP-deficient tumours that may qualify for emerging targeted therapy.

• Across 2,409 exome-sequenced tumours, MTAP IHC agreed with sequencing for clear wild-type and homozygous-deletion calls.
• IHC reclassified many indeterminate 'heterozygous' sequencing calls, with protein loss matching homozygous deletion on FISH.
• The indeterminate calls were not explained by low tumour cellularity.
• Use MTAP IHC, with FISH confirmation where needed, to resolve equivocal sequencing before selecting for PRMT5–MAT2A-axis therapy.

Why it matters

It gives labs a cheap, quick way to rescue the equivocal molecular result that would otherwise delay or misdirect targeted-therapy selection.

Don't overread it

This is about resolving an assay ambiguity and selecting for emerging therapies — it is not evidence that any specific MTAP-directed drug improves outcomes.

The statistics, in plain English

Concordance here means the protein-level and genomic calls agreed; the clinically important move is that IHC turned a large fraction of uncertain 'heterozygous' sequencing results into definite calls, which a copy-number score alone could not do.

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