Chromosomal co-deletion confounds PTEN-linked glutaminolysis biomarkers
Investigators analyzed TCGA PanCancer Atlas and DepMap CRISPR datasets to determine whether a five-gene glutaminolysis signature correlates with PTEN loss or is driven by genomic location. The study reports that the signature's apparent association with PTEN deletion was predominantly a passenger effect caused by co-deletion of neighboring chromosome-10 genes, with no independent MYC mediation or consistent functional dependence across PTEN dosage tiers. This finding demonstrates that PTEN copy number alone is an unreliable proxy for glutaminolytic pathway activity and highlights a broader validation hazard for multi-gene diagnostic signatures anchored to frequently co-deleted loci. The authors propose a four-step screening framework to decompose signatures by chromosomal position and condition on individual gene copy numbers, offering a practical safeguard for molecular diagnostics developers and laboratory directors designing or interpreting genomic biomarkers.
The original study
Passenger co-deletion confounds glutaminolysis signatures anchored on PTEN loss: A cautionary case for location-aware signature design.
- Authors
- Abusneina AM, Elwirfli SM
- Journal
- PloS one
- Type
- Journal Article
- PMID
- 42853860
Original abstract
PTEN-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 PTEN 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 PTEN intact, hemizygous, or homozygous deletion, and scored a five-gene glutaminolysis signature (GLS, SLC1A5, GOT1, GLUD1, GPT2) against loss severity across fourteen tumor types, testing MYC mediation and chromosome-10 co-deletion as alternative mechanisms, with GLS dependence assessed in DepMap CRISPR data. The signature decreased with PTEN loss in all fourteen types, significantly in twelve, but was not MYC-mediated. The decline tracked chromosomal position rather than pathway membership: GLUD1 and GOT1 flank PTEN on 10q, and thirty-seven neighboring genes carrying no glutaminolysis annotation tracked PTEN copy number just as closely (mean rho 0.843 compared with 0.842), with co-deletion fidelity falling monotonically with distance from PTEN (rho = -0.993). Adjustment for genome-wide aneuploidy left the association intact, whereas conditioning on each gene's own copy number abolished it for the chromosome-10 genes and left the others unchanged. In a natural experiment contrasting PTEN point-mutant, copy-neutral tumors with copy-neutral wild-type tumors, GLUD1 was lower in the mutant group when all cohorts were pooled (P = 1.0 x 10^-8), an effect attributable to endometrial carcinoma, the one lineage in which mutation alone lowered GLUD1; excluding that lineage in a post hoc sensitivity analysis left no detectable difference (P = 0.22, equivalence P = 0.015), whereas hemizygous and homozygous deletion lowered GLUD1 dose-dependently in every analysis. GLS 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, ERG status and proliferation, opposite in direction to the signaling prediction; breast and stomach showed small positive associations. The inverse PTEN-glutaminolysis relationship in this transcript signature is therefore explained predominantly by passenger co-deletion rather than by a PTEN-linked metabolic program, making PTEN 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's own copy number against the driver's; compare driver-mutant copy-neutral tumors with copy-neutral wild-type tumors; and check the inferred pathway activity against an independent functional readout.