Genomics of MTAP Loss in >500,000 Solid Tumor Specimens Profiled Using Comprehensive Genomic Profiling Platforms

PURPOSE Methylthioadenosine phosphorylase (MTAP) genomic loss is an emerging biomarker for PRMT5 and MAT2A inhibitors based on synthetic lethality. The MTAP gene is located on chromosome 9p21. 3 near CDKN2A/B. MTAP homozygous loss across tumor types, specific exons lost, MTAP expression, and the landscape of coalterations were assessed. METHODS 409, 755 tissue biopsies (TBx) and 85, 801 liquid biopsies (LBx) were sequenced using hybrid capture–based NGS (FoundationOne CDx or FoundationOne Liquid CDx), evaluating all classes of genomic alterations and circulating tumor DNA (ctDNA) tumor fraction (TF). Additionally, 6, 740 TBx were subjected to both RNA and DNA sequencing to compare MTAP gene expression with genomic MTAP loss. RESULTS The prevalence of pan-tumor MTAP loss was 11. 4% using TBx, with the highest prevalence observed in mesothelioma (32. 8%), glioma (32. 7%), pancreatic (28. 9%), and bladder cancers (26. 4%). Prevalence of MTAP loss on LBx approximated that of TBx when ctDNA TF ≥20% (positive percent agreement PPA = 86. 2%). CDKN2A loss was not a reliable proxy for MTAP loss ; 33. 7% of CDKN2A loss cases did not have MTAP loss. MTAP loss was enriched with CDKN2A/B losses pan-tumor, EGFR in NSCLC, ERBB2 in colorectal cancer, and PTEN in prostate cancer, while MTAP no_ loss was enriched for RB1 pan-tumor, APC in colorectal cancer, CCNE1 in breast and ovarian cancer, and SPOP in prostate cancer. Complete loss (exons 1-8) was observed in 82. 9%, multiple exons in 16. 5% and exon 8 alone in <1%. MTAP loss, specifically the number of exons lost, was correlated with reduced RNA expression. CONCLUSION MTAP loss is a frequent pan-tumor alteration that predicts potential sensitivity to PRMT5 or MAT2A inhibitors. Although most tumors exhibit complete MTAP loss, 16. 5% are characterized by partial MTAP loss where clinical benefit remains uncertain. The genomic coalteration landscape reported here may inform future PRMT5 or MAT2A clinical trials, potentially in combination with other agents.