- Design
- Pan-cancer concordance study of whole-exome sequencing against immunohistochemistry, FISH and RNA sequencing
- Population
- 2,409 tumours profiled in the EXOMA2 study, with a subset with tissue for orthogonal testing
- Primary outcome
- Concordance of MTAP immunohistochemistry with genomic copy number classification
- Effect
- High concordance in wild-type and homozygous deletion; immunohistochemistry reclassified a substantial proportion of heterozygous sequencing calls (exact proportion not given in the abstract)
In a cohort of 2,409 tumours profiled by whole-exome sequencing, investigators classified MTAP copy number as wild-type, homozygous deletion or probable heterozygous deletion with two algorithms. A subset with tissue was tested by immunohistochemistry with three antibody clones, and selected cases by FISH and RNA sequencing.
Immunohistochemistry agreed closely with genomic classification in wild-type and homozygously deleted tumours. It also reclassified a substantial share of the tumours called heterozygous by sequencing, where loss of protein matched homozygous deletion confirmed by FISH. The heterozygous calls were not explained by low tumour cellularity.
MTAP loss is of interest as a biomarker for emerging PRMT5-MAT2A pathway inhibitors. The abstract gives no figure for how many calls were reclassified, so laboratories should validate locally. The authors suggest immunohistochemistry with FISH confirmation as a faster, cheaper route to patient selection, but no treatment benefit was tested here.
- Immunohistochemistry matched sequencing in wild-type and homozygous deleted tumours.
- It reclassified many borderline heterozygous sequencing calls.
- Low tumour purity did not explain the ambiguous calls.
- Three antibody clones were tested; validate whichever you use.
- Confirm discordant results with FISH.
Why it matters
Ambiguous sequencing calls can block access to a biomarker-selected trial or therapy, and a cheap stain can help resolve them.
Don't overread it
The study shows analytic concordance, not that selecting patients by MTAP status improves outcomes.
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