Genomic and biomarker landscape of MTAP deficiency in gastrointestinal cancers.

4175 Background: Genomic loss of MTAP and CDKN2A is frequently observed across cancers, with ongoing development of MTA-selective PRMT5 inhibitors aiming to achieve synthetic lethality in the setting of MTAP loss. However, the biomarker landscape of patients with gastrointestinal (GI) cancers and MTAP deficiency remains poorly defined, and whether subsets of GI cancers harbor non-genomic mechanisms of MTAP deficiency remains unknown. Methods: All GI cancer samples sequenced with MSK-IMPACT v7, a DNA-based next generation sequencing (NGS) panel with coverage for MTAP / CDKN2A were queried. MTAP and CDKN2A deletions (del) were defined by low read counts in coverage-based copy number analyses. Genomic and pathologic analyses were completed in tumors with high MTAP del prevalence: esophagogastric cancers (EGC), pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNETs), and biliary tract cancers (BTCs). MTAP immunohistochemistry (IHC) was completed on PDAC, PanNET, small bowel NET, and BTC samples to investigate prevalence of MTAP protein loss. Results: Among 8346 GI cancer samples, MTAP del was identified in 456 (5.5%), co-occurring with CDKN2A del in 98.8% of cases, with 79.8% confirmed homozygous del by FACETS, and was associated with higher tumor purity compared to MTAP -intact samples (p < 0.001). MTAP del prevalence was 14.4% in esophageal squamous cell carcinoma (SCC), 5.9% in esophagogastric adenocarcinoma (EGA), 12.4% in PDAC, 7.4% in PanNET (grade 1 [G1]: 3.4%, G2: 4.3%, G3: 19.4%), 0% in small bowel NET, 10.2% in BTCs (including 11.5% in intrahepatic cholangiocarcinoma [iCCA]), and 0.7% in colorectal cancer. MTAP del was associated with wild-type (WT) KRAS amplifications (amp) in EGC, KRAS G12V and WT KRAS amp in PDAC, and KRAS mutations and FGFR2 fusions in iCCA. Among EGA, PDAC, and BTCs, MTAP del tumors were associated with higher fractions of genome altered (p < 0.001 for each) and rates of whole genome duplication (p < 0.001 for each). Among 463 samples profiled by MTAP IHC, MTAP deficiency was found in 29/93 (31%) PDAC, 3/33 (11%) BTC, 15/60 (25%) PanNETs, and 196/277 (71%) small bowel NETs. Analysis of MTAP deficiency and activity of standard systemic therapies, as well as metabolomic and epigenomic profiling of MTAP-deficient GI cancers are ongoing and will be presented. Conclusions: MTAP genomic del are recurrently identified across GI cancers, most notably in esophageal SCC, PDAC, G3 pancreatic NETs, and iCCA. MTAP del are associated with distinct genomic drivers across GI cancers and markers of chromosomal instability more broadly. We found evidence of discrepancy between MTAP loss by NGS and IHC across multiple GI cancers, most notably small bowel NETs, which demonstrate frequent MTAP IHC deficiency in complete absence of genomic loss, suggesting non-genomic mechanisms of MTAP silencing. These observations may help define the role for therapies targeting MTAP deficiency in GI cancers.