MTAP loss in lung cancer: immunohistochemistry catches what low-purity sequencing misses

The edition in brief

MTAP loss is becoming a predictive biomarker as drugs targeting the metabolic vulnerability it creates move through trials. An institutional review of 5,233 non-small cell lung cancers with NGS found homozygous MTAP deletion in 5.6%, enriched in never or light smokers and in tumours with EGFR mutations or ALK fusions. In 105 cases tested both ways, IHC and NGS agreed in 97.3% after excluding sequencing from samples with 30% tumour or less; IHC was more sensitive with low tumour content or subclonal loss, and about 13% of losses stained heterogeneously. A whole-exome and transcriptome study of 90 intrahepatic cholangiocarcinomas found FGFR2/3 alterations in 28%, almost all in younger patients with large, well-differentiated, non-mucinous, small-duct tumours and fewer TP53 and KRAS mutations; the survival advantage did not hold after adjustment, so it reflects the phenotype rather than FGFR status itself. In PSC with inflammatory bowel disease, aberrant p53 overexpression in benign biopsies taken a mean of 20 months before dysplasia was found in 36% of patients who later developed dysplasia and 5% of controls — specific (95%) but insensitive (36%), and from 45 patients. The pearl covers pre-analytical timings for breast biomarker testing.