{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:57:39Z","timestamp":1791568659308,"version":"4.3.4"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T00:00:00Z","timestamp":1791504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"\n PTEN<\/jats:italic>\n -deficient tumors are widely assumed to be glutamine-dependent, a view that has helped motivate the clinical development of glutaminase inhibitors. Whether glutaminolytic transcription scales with\n PTEN<\/jats:italic>\n copy-number loss in human tumors, and by what mechanism, has not been established. We classified TCGA PanCancer Atlas tumors by GISTIC copy number as\n PTEN<\/jats:italic>\n intact, hemizygous, or homozygous deletion, and scored a five-gene glutaminolysis signature (\n GLS<\/jats:italic>\n ,\n SLC1A5<\/jats:italic>\n ,\n GOT1<\/jats:italic>\n ,\n GLUD1<\/jats:italic>\n ,\n GPT2<\/jats:italic>\n ) against loss severity across fourteen tumor types, testing\n MYC<\/jats:italic>\n mediation and chromosome-10 co-deletion as alternative mechanisms, with\n GLS<\/jats:italic>\n dependence assessed in DepMap CRISPR data. The signature decreased with\n PTEN<\/jats:italic>\n loss in all fourteen types, significantly in twelve, but was not\n MYC<\/jats:italic>\n -mediated. The decline tracked chromosomal position rather than pathway membership:\n GLUD1<\/jats:italic>\n and\n GOT1<\/jats:italic>\n flank\n PTEN<\/jats:italic>\n on 10q, and thirty-seven neighboring genes carrying no glutaminolysis annotation tracked\n PTEN<\/jats:italic>\n copy number just as closely (mean rho 0.843 compared with 0.842), with co-deletion fidelity falling monotonically with distance from\n PTEN<\/jats:italic>\n (rho\u2009=\u2009\u22120.993). Adjustment for genome-wide aneuploidy left the association intact, whereas conditioning on each gene\u2019s own copy number abolished it for the chromosome-10 genes and left the others unchanged. In a natural experiment contrasting\n PTEN<\/jats:italic>\n point-mutant, copy-neutral tumors with copy-neutral wild-type tumors,\n GLUD1<\/jats:italic>\n was lower in the mutant group when all cohorts were pooled (P\u2009=\u20091.0 x 10^-8), an effect attributable to endometrial carcinoma, the one lineage in which mutation alone lowered\n GLUD1<\/jats:italic>\n ; excluding that lineage in a post hoc sensitivity analysis left no detectable difference (P\u2009=\u20090.22, equivalence P\u2009=\u20090.015), whereas hemizygous and homozygous deletion lowered\n GLUD1<\/jats:italic>\n dose-dependently in every analysis.\n GLS<\/jats:italic>\n dependence did not differ across dosage tiers. Prostate carcinoma was the sole departure in the negative direction, its off-chromosome-10 decline surviving adjustment for tumor purity, stage,\n ERG<\/jats:italic>\n status and proliferation, opposite in direction to the signaling prediction; breast and stomach showed small positive associations. The inverse\n PTEN<\/jats:italic>\n -glutaminolysis relationship in this transcript signature is therefore explained predominantly by passenger co-deletion rather than by a\n PTEN<\/jats:italic>\n -linked metabolic program, making\n PTEN<\/jats:italic>\n copy number unreliable as a stand-alone glutaminolysis biomarker and illustrating a general hazard: any signature scored against a frequently co-deleted locus can be confounded by where its genes sit. We provide a four-step screening procedure: decompose the signature by chromosomal position relative to the driver; test each constituent gene\u2019s own copy number against the driver\u2019s; compare driver-mutant copy-neutral tumors with copy-neutral wild-type tumors; and check the inferred pathway activity against an independent functional readout.\n <\/jats:p>","DOI":"10.1371\/journal.pone.0354937","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T17:33:56Z","timestamp":1791567236000},"page":"e0354937","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Passenger co-deletion confounds glutaminolysis signatures anchored on PTEN loss: A cautionary case for location-aware signature design"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9909-5588","authenticated-orcid":true,"given":"Abdelmuhsen M.","family":"Abusneina","sequence":"first","affiliation":[{"name":"University of Benghazi","place":["Benghazi, Libya"],"department":["Department of Molecular Diagnostics, Faculty of Biomedical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5103-0290","authenticated-orcid":true,"given":"Soad M.","family":"Elwirfli","sequence":"additional","affiliation":[{"name":"University of Benghazi","place":["Benghazi, Libya"],"department":["Department of Forensic Sciences, Faculty of Biomedical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,9]]},"reference":[{"issue":"7","key":"pone.0354937.ref001","article-title":"Glutamine metabolism: Molecular regulation, biological functions, and diseases","volume":"6","author":"MA Kumar","year":"2025","journal-title":"MedComm (2020)"},{"issue":"10","key":"pone.0354937.ref002","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1001\/jamaoncol.2022.3511","article-title":"Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: The CANTATA randomized clinical trial","volume":"8","author":"NM Tannir","year":"2022","journal-title":"JAMA Oncol"},{"issue":"2","key":"pone.0354937.ref003","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.cell.2010.12.020","article-title":"Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner","volume":"144","author":"MS Song","year":"2011","journal-title":"Cell"},{"issue":"12","key":"pone.0354937.ref004","doi-asserted-by":"crossref","first-page":"18832","DOI":"10.18632\/oncotarget.13600","article-title":"Selenite inhibits glutamine metabolism and induces apoptosis by regulating GLS1 protein degradation via APC\/C-CDH1 pathway in colorectal cancer cells","volume":"8","author":"J Zhao","year":"2017","journal-title":"Oncotarget"},{"issue":"5","key":"pone.0354937.ref005","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/ng.556","article-title":"Subtle variations in Pten dose determine cancer susceptibility","volume":"42","author":"A Alimonti","year":"2010","journal-title":"Nat Genet"},{"issue":"32","key":"pone.0354937.ref006","doi-asserted-by":"crossref","first-page":"5317","DOI":"10.2174\/0929867326666190416165004","article-title":"Metabolic reprogramming of cancer by chemicals that target glutaminase isoenzymes","volume":"27","author":"JM Mat\u00e9s","year":"2020","journal-title":"Curr Med Chem"},{"issue":"1","key":"pone.0354937.ref007","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cell.2012.02.030","article-title":"Systemic elevation of PTEN induces a tumor-suppressive metabolic state","volume":"149","author":"I Garcia-Cao","year":"2012","journal-title":"Cell"},{"issue":"5","key":"pone.0354937.ref008","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"E Cerami","year":"2012","journal-title":"Cancer Discov"},{"issue":"269","key":"pone.0354937.ref009","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"J Gao","year":"2013","journal-title":"Sci Signal"},{"issue":"3","key":"pone.0354937.ref010","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2017.06.010","article-title":"Defining a cancer dependency map","volume":"170","author":"A Tsherniak","year":"2017","journal-title":"Cell"},{"issue":"4","key":"pone.0354937.ref011","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2011-12-4-r41","article-title":"GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers","volume":"12","author":"CH Mermel","year":"2011","journal-title":"Genome Biol"},{"issue":"1","key":"pone.0354937.ref012","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1186\/s13059-021-02540-7","article-title":"Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects","volume":"22","author":"JM Dempster","year":"2021","journal-title":"Genome Biol"},{"issue":"48","key":"pone.0354937.ref013","doi-asserted-by":"crossref","first-page":"18782","DOI":"10.1073\/pnas.0810199105","article-title":"Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction","volume":"105","author":"DR Wise","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pone.0354937.ref014","doi-asserted-by":"crossref","first-page":"5049","DOI":"10.1038\/s41598-023-31759-6","article-title":"Pan-cancer genomic analysis shows hemizygous PTEN loss tumors are associated with immune evasion and poor outcome","volume":"13","author":"T Vidotto","year":"2023","journal-title":"Sci Rep"},{"issue":"3","key":"pone.0354937.ref015","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s11515-017-1443-5","article-title":"PTEN at the interface of immune tolerance and tumor suppression","volume":"12","author":"A Brandmaier","year":"2017","journal-title":"Front Biol (Beijing)"},{"key":"pone.0354937.ref016","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.3390\/cells9071725","article-title":"The tumor suppressor PTEN as molecular switch node regulating cell metabolism and autophagy","volume":"9","author":"S Aquila","year":"2020","journal-title":"Cells"},{"issue":"51","key":"pone.0354937.ref017","doi-asserted-by":"crossref","first-page":"84999","DOI":"10.18632\/oncotarget.13113","article-title":"PTEN dephosphorylates AKT to prevent the expression of GLUT1 on plasmamembrane and to limit glucose consumption in cancer cells","volume":"7","author":"S Phadngam","year":"2016","journal-title":"Oncotarget"},{"issue":"19","key":"pone.0354937.ref018","doi-asserted-by":"crossref","first-page":"3642","DOI":"10.1128\/MCB.00814-14","article-title":"Plk1 phosphorylation of PTEN causes a tumor-promoting metabolic state","volume":"34","author":"Z Li","year":"2014","journal-title":"Mol Cell Biol"},{"issue":"9","key":"pone.0354937.ref019","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/s41580-018-0015-0","article-title":"The functions and regulation of the PTEN tumour suppressor: new modes and prospects","volume":"19","author":"Y-R Lee","year":"2018","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"11","key":"pone.0354937.ref020","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1038\/s12276-022-00887-w","article-title":"The equilibrium of tumor suppression: DUBs as active regulators of PTEN","volume":"54","author":"A Christine","year":"2022","journal-title":"Exp Mol Med"},{"issue":"5","key":"pone.0354937.ref021","doi-asserted-by":"crossref","first-page":"112536","DOI":"10.1016\/j.celrep.2023.112536","article-title":"AKT activation because of PTEN loss upregulates xCT via GSK3\u03b2\/NRF2, leading to inhibition of ferroptosis in PTEN-mutant tumor cells","volume":"42","author":"KM Cahuzac","year":"2023","journal-title":"Cell Rep"},{"issue":"28","key":"pone.0354937.ref022","doi-asserted-by":"crossref","first-page":"26161","DOI":"10.18632\/oncotarget.4544","article-title":"Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression","volume":"6","author":"X Xu","year":"2015","journal-title":"Oncotarget"},{"issue":"4","key":"pone.0354937.ref023","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1158\/2159-8290.CD-16-0612","article-title":"PTEN regulates glutamine flux to pyrimidine synthesis and sensitivity to dihydroorotate dehydrogenase inhibition","volume":"7","author":"D Mathur","year":"2017","journal-title":"Cancer Discov"},{"issue":"7","key":"pone.0354937.ref024","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1182\/bloodadvances.2024013762","article-title":"ATP citrate lyase is an essential player in the metabolic rewiring induced by PTEN loss during T-ALL development","volume":"9","author":"GP Andrieu","year":"2025","journal-title":"Blood Adv"},{"issue":"10","key":"pone.0354937.ref025","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1038\/nm.3955","article-title":"Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia","volume":"21","author":"D Herranz","year":"2015","journal-title":"Nat Med"},{"issue":"12","key":"pone.0354937.ref026","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1038\/leu.2017.160","article-title":"Control of amino acid transport coordinates metabolic reprogramming in T-cell malignancy","volume":"31","author":"KM Grzes","year":"2017","journal-title":"Leukemia"},{"issue":"1","key":"pone.0354937.ref027","doi-asserted-by":"crossref","first-page":"2","DOI":"10.31083\/j.fbe1501002","article-title":"Targeting glutamine metabolism in prostate cancer","volume":"15","author":"N Bhowmick","year":"2023","journal-title":"Front Biosci (Elite Ed)"},{"issue":"16","key":"pone.0354937.ref028","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.3390\/cancers16162871","article-title":"Glutamine metabolism and prostate cancer","volume":"16","author":"HHH Erb","year":"2024","journal-title":"Cancers 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