Genomic Landscape and Clinical Impact of MTAP Loss in Driver-Positive NSCLC: Insights From a Large-Scale Real-World
Qianhui Wei1, Youhui Wang1, Ting Hou2
1Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, People's Republic of China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, People's Republic of China; Tianjin's Clinical Research Center for Cancer, Tianjin, People's Republic of China; Center for Precision Cancer Medicine and Translational Research, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, People's Republic of China.
Introduction:
MTAP loss is a frequent genomic event in NSCLC, yet its clinical and therapeutic implications in oncogene-driven disease remain incompletely understood.
Methods:
We analyzed genomic profiles of 6492 Chinese patients with NSCLC from a real-world database and evaluated survival outcomes in 173 treatment-naïve, driver-positive patients receiving first-line targeted therapies. Associations of MTAP loss with clinicopathologic characteristics, co-mutations, and outcomes were assessed, with particular attention to its interplay with CDKN2A loss.
Results:
MTAP loss was identified in 10.4% of the overall cohort and was enriched in advanced stage and tumors harboring oncogenic drivers, including EGFR mutations, ALK fusions, and amplifications of MET and ERBB2. Co-deletion with CDKN2A was highly prevalent in MTAP-loss tumors (92.3%). Structurally, MTAP loss was predominantly complete (87.8%), with the remaining cases mainly comprising partial losses involving exon 8 (10.6%). A high concordance (92.1%) was observed between next-generation sequencing and immunohistochemistry for the identification of MTAP loss. In driver-positive patients, MTAP loss was associated with a lower response rate and shorter progression-free survival and overall survival, especially in EGFR-mutant patients treated with third-generation EGFR-tyrosine kinase inhibitors. Combined MTAP/CDKN2A analysis revealed a prognostic gradient, with dual loss conferring the worst outcomes and remaining an independent predictor in multivariable models.
Conclusions:
MTAP loss defines a distinct molecular subset of NSCLC and serves as a robust adverse prognostic biomarker in EGFR-mutant disease treated with targeted therapies. These findings support integrating MTAP status into risk stratification and exploring combination strategies that incorporate PRMT5 or MAT2A inhibition.
Insights
Methylthioadenosine phosphorylase (MTAP) loss is common in non-small cell lung cancer (NSCLC). MTAP loss indicates worse outcomes for patients receiving targeted therapy, especially those with EGFR mutations.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Methylthioadenosine phosphorylase (MTAP) loss is a frequent genomic event in non-small cell lung cancer (NSCLC).
- Its clinical and therapeutic implications in oncogene-driven NSCLC are not fully understood.
Purpose of the Study:
- To investigate the clinical significance of MTAP loss in a large cohort of Chinese NSCLC patients.
- To evaluate the association of MTAP loss with clinicopathologic features, co-mutations, and survival outcomes in patients receiving targeted therapies.
Main Methods:
- Analysis of genomic profiles from 6,492 Chinese NSCLC patients.
- Evaluation of survival outcomes in 173 treatment-naïve, driver-positive patients receiving first-line targeted therapies.
- Assessment of MTAP loss using next-generation sequencing (NGS) and immunohistochemistry (IHC), with attention to co-deletion with CDKN2A.
Main Results:
- MTAP loss occurred in 10.4% of NSCLC patients and was enriched in advanced stages and driver-mutated tumors.
- MTAP loss, particularly co-deletion with CDKN2A, was associated with significantly lower response rates and shorter progression-free survival (PFS) and overall survival (OS).
- MTAP loss served as an independent adverse prognostic biomarker in EGFR-mutant NSCLC treated with third-generation EGFR-TKIs.
Conclusions:
- MTAP loss identifies a distinct molecular subset of NSCLC with poor prognosis.
- MTAP status is a robust adverse prognostic biomarker in EGFR-mutant NSCLC treated with targeted therapy.
- Integrating MTAP status into risk stratification and exploring combination therapies targeting PRMT5 or MAT2A are recommended.