Abstract 1121: Pan-cancer prevalence of unusual MTAP alterations: data from the AACR GENIE database

Abstract Background: PRMT5 inhibitors has shown promising clinical activity in MTAP deficient tumors. Ongoing studies focus on tumors with homozygous MTAP deletions; but that doesn’t span the whole spectrum of MTAP dysfunctional tumors. Herein, we tried to characterize the pan-cancer prevalence of MTAP oncogenic alterations. Methods: We used the AACR GENIE database v.16.1 to extract data on the prevalence of MTAP alterations across different tumor types. OncoKB was used to obtain data on functional significance. Results: We reviewed data from 214, 475 samples obtained from 184, 980 patients. Structural variants, mutations, and copy number alterations in MTAP were profiled in 55, 021, 58, 144, and 57, 382 samples across different cancers; respetively. A total of 46 MTAP fusions were identified; all were likely oncogenic per OncoKB including 12 with level 4 alterations. The most common fusions were MTAP intragenic, MTAP::CDKN2A, and MTAP::CDKN2B fusions. The highest rates of MTAP structural variants were observed in CNS cancers (0.4%; n=1), gastrointestinal neuroendocrine tumor (0.3%; n=1), hepatobiliary cancer (0.2%; n=3), melanoma (0.2%; n=3), and glioma (0.1%; n=5). A total of 356 MTAP mutations were identified; including 82 that were likely oncogenic per OncoKB. The most common mutations that were annotated as likely oncogenic were MTAP A191Rfs*6, MTAP X231_splice, and MTAP X116_splice. The highest rates of MTAP mutations were observed in endometrial cancer (1.6%; n=36), small bowel cancer (1.6%; n=3), non-melanoma skin cancer, (1.5%; n=6), colorectal cancer (1.2%; n=72), and bladder cancer (1%; n=20). The highest rates of MTAP homozygous deletions were observed in glioma (24.6%; n=899), blastic plasmacytoid dendritic cell neoplasm (23.1%; n=3), nerve sheath tumor (18.3%; n=28), mesothelioma (17.7%; n=79), and bladder cancer (16.9%; n=350) (Table 1). Conclusions: The spectrum of MTAP alterations expands beyond MTAP deletions; and could be explored in clinical trials targeting MTAP loss. Citation Format: Mohamed A. Gouda, Camila B. Xavier, Carlos Torrado, Pooja A. Shah, Kunal Rai, Natalie Vokes, Omar Alhalabi, Mark T. Bedford, Jianjun Gao, Nazanin K. Majd, Jenny Li, Milind Javle, Funda Meric-Bernstam, Jordi Rodon. Pan-cancer prevalence of unusual MTAP alterations: data from the AACR GENIE database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1121.