# Real-World Prevalence and Structural Validation of the Canonical 9p21 MTAP–CDKN2A/B Deletion in Non-NSCLC Solid Tumors

## TL;DR

This study examines how often a specific genetic deletion involving the MTAP gene occurs in various solid tumors and finds it is rare but consistently linked to other nearby gene losses.

## Contribution

The study provides real-world genomic evidence that MTAP deletion is a distinct molecular subset of solid tumors with a canonical 9p21 co-deletion pattern.

## Key findings

- MTAP deletion was found in 2.4% of 579 non-NSCLC solid tumor cases.
- MTAP deletion consistently co-occurred with loss of neighboring genes CDKN2A and CDKN2B at chromosome 9p21.
- All MTAP-deleted tumors were microsatellite stable and had low mutation burden.

## Abstract

Deletion of the MTAP gene is a genomic alteration of growing clinical interest because new targeted therapies are being developed for cancers with this feature. However, information on its frequency and genomic structure in non-NSCLC solid tumors from real-world clinical practice remains limited. In this study, we analyzed next-generation sequencing data from 579 patients with non-NSCLC solid tumors. MTAP deletion was uncommon but consistently occurred together with loss of neighboring tumor suppressor genes at chromosome 9p21, forming a spatially clustered deletion pattern centered on the 9p21 locus. This finding was observed across several cancer types, including sarcoma, pancreatic cancer, and urothelial carcinoma. In addition, all MTAP-deleted tumors showed low mutation burden and stable microsatellite status. These results provide real-world genomic evidence supporting MTAP deletion as a distinct molecular subset of solid tumors and highlight the value of comprehensive genomic profiling for identifying patients who may benefit from emerging MTAP-targeted therapies.

Background: Deletion of the MTAP gene at chromosome 9p21.3 defines a therapeutically actionable molecular subset of cancers due to synthetic lethal vulnerability to PRMT5 and MAT2A inhibition. The real-world prevalence and genomic context of MTAP deletion in diverse solid tumors remain incompletely characterized. Methods: We retrospectively analyzed 579 solid tumor specimens subjected to next-generation sequencing-based copy-number profiling. The prevalence of MTAP deletion and its co-occurrence with CDKN2A and CDKN2B were evaluated, and genomic deletion patterns across chromosome 9 were systematically assessed. Results: MTAP deletion was detected in 14 cases (2.4%, 95% confidence interval [CI], 1.45–4.02%), with enrichment in sarcoma, pancreatic cancer, and urothelial carcinoma. Concurrent CDKN2A loss was observed in 92.9% of MTAP-deleted tumors, and 64.3% showed additional CDKN2B loss, indicating a coordinated focal deletion event at 9p21.3. Statistical analyses confirmed strong genomic associations between MTAP and neighboring tumor suppressor genes. Across the full cohort, deletion frequency peaked at the 9p21 locus, and among MTAP-deleted tumors, co-deletion frequency decreased with increasing genomic distance. All MTAP-deleted tumors were microsatellite stable and low tumor mutational burden (TMB-low). Conclusions: Our findings demonstrate that MTAP deletion is an infrequent but genomically coherent event in solid tumors, characterized by a canonical 9p21 co-deletion pattern. This real-world analysis underscores the importance of comprehensive genomic profiling to identify patients who may benefit from emerging MTAP-directed therapies.