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

Abstract

Methylthioadenosine phosphorylase (<i>MTAP</i>) genomic loss is an emerging biomarker for PRMT5 and MAT2A inhibitors based on synthetic lethality. The <i>MTAP</i> gene is located on chromosome 9p21.3 near <i>CDKN2A/B. MTAP</i> homozygous loss across tumor types, specific exons lost, <i>MTAP</i> expression, and the landscape of coalterations were assessed. 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 <i>MTAP</i>_loss. The prevalence of pan-tumor <i>MTAP</i>_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 <i>MTAP</i>_loss on LBx approximated that of TBx when ctDNA TF ≥20% (positive percent agreement [PPA] = 86.2%). <i>CDKN2A</i>_loss was not a reliable proxy for <i>MTAP</i>_loss; 33.7% of <i>CDKN2A</i>_loss cases did not have <i>MTAP</i>_<i>loss</i>. <i>MTAP</i>_loss was enriched with <i>CDKN2A/B</i> losses pan-tumor, <i>EGFR</i> in NSCLC, <i>ERBB2</i> in colorectal cancer, and <i>PTEN</i> in prostate cancer, while <i>MTAP</i>_{<i>no_</i>}_loss was enriched for <i>RB1</i> pan-tumor, <i>APC</i> in colorectal cancer, <i>CCNE1</i> in breast and ovarian cancer, and <i>SPOP</i> in prostate cancer. Complete loss (exons 1-8) was observed in 82.9%, multiple exons in 16.5% and exon 8 alone in <1%. <i>MTAP</i>_loss, specifically the number of exons lost, was correlated with reduced RNA expression. <i>MTAP</i>_loss is a frequent pan-tumor alteration that predicts potential sensitivity to PRMT5 or MAT2A inhibitors. Although most tumors exhibit complete <i>MTAP</i>_loss, 16.5% are characterized by partial <i>MTAP</i>_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.