{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMTAP is a ubiquitously expressed enzyme located on chromosome 9p21 that plays a critical role in the methionine and adenine salvage pathways. By catalyzing the reversible phosphorolytic cleavage of methylthioadenosine (MTA)—a by‐product of polyamine biosynthesis—MTAP helps regulate intracellular levels of polyamines and S-adenosylmethionine. Loss or inactivation of MTAP perturbs this balance, resulting in MTA accumulation and altered polyamine metabolism that have been linked to enhanced tumorigenicity. Moreover, experimental re-expression of MTAP in tumor cell models has been shown to suppress anchorage-independent growth and invasion, highlighting its function as a tumor suppressor in diverse settings such as breast adenocarcinoma, hepatocellular carcinoma, and other cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn many tumor types MTAP is frequently inactivated—either by homozygous deletion, promoter hypermethylation, or even by generation of fusion transcripts—and its loss is commonly associated with the deletion of adjacent tumor suppressor genes such as CDKN2A. Such co-deletions have been documented in melanocytic lesions, pancreatic adenocarcinomas, mesotheliomas, lung cancers, gliomas, and other malignancies, where diminished MTAP expression serves as both a diagnostic surrogate (for example, by immunohistochemistry in mesothelial proliferations) and an adverse prognostic marker. Genetic studies have further linked MTAP polymorphisms with higher numbers of nevi and increased melanoma risk, while integrative genomic and methylation analyses in diverse cancers—including nasopharyngeal carcinoma, chondrosarcoma, prostate and colorectal cancers—support a role for MTAP loss in promoting aggressive disease phenotypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies have also identified exploitable vulnerabilities in MTAP-deficient tumors. The accumulation of MTA in cells lacking MTAP activity leads to the selective inhibition of protein arginine methyltransferase 5 (PRMT5) and renders these cells highly sensitive to the suppression of MAT2A—the enzyme responsible for producing S-adenosylmethionine—and to other inhibitors targeting de novo purine synthesis. Such synthetic lethal approaches have been successfully demonstrated in preclinical models of lung cancer and other malignancies, suggesting promising therapeutic strategies for selectively targeting MTAP-deleted cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}, {"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Scott A Christopher, Paula Diegelman, Carl W Porter, et al. 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