Dysregulation of DNA damage repair in lung cancer driven by <i>MTAP</i> loss: Mechanistic insights and target discovery.

Abstract

8602 Background: MTAP loss leads to methylthioadenosine (MTA) accumulation, disrupting downstream metabolic pathways. Targeting synthetic lethal interactions with MTAP loss offers a promising therapeutic strategy. The DNA damage response (DDR) pathway, essential for genomic stability, is commonly dysregulated in lung cancer, impacting treatment response and prognosis. Emerging evidence has highlighted potential association between MTAP loss and mutations in DDR genes, suggesting that investigating their relationship is critical for uncovering disease mechanisms and identifying novel biomarkers and therapeutic targets. Methods: Hybridization capture sequencing with StarPanel NGS Assay (1,326 genes) was conducted on 2,258 Chinese lung cancer patients' tumor and matched peripheral blood samples. Then somatic and germline mutations, and TMB values of each sample were obtained. Based on a depth-based algorithm, differences between tissue and control samples in CNVs from the gene level were analyzed. Besides, we utilized shifts in germline heterozygous SNPs within the gene region to assist in determining if the loss was homozygous or heterozygous. Results: Homozygous and heterozygous deletions of MTAP were detected in 11.07% and 6.95% of all samples. Notably, 61.67% of these samples exhibited co-loss of MTAP , CDKN2A and CDKN2B . The median TMB was significantly higher in samples with MTAP loss (3.85 mut/Mb) compared to those with intact MTAP (2.56 mut/Mb). In samples with homozygous MTAP loss, the top somatically co-altered genes were EGFR (76.00%), TP53 (57.60%) and CDKN2A (52.80%). Gain-of-function (GoF) mutations were most prevalent in EGFR (56.80%), KRAS (12.00%) and MDM2 (10.00%), while Loss-of-function (LoF) mutations were most common in TP53 (50.40%), RBM10 (11.60%) and PTEN (7.60%). Notably, LoF mutations in MTAP -loss samples showed a higher prevalence of DDR genes compared to MTAP -intact samples, including RAD50 (2.40% vs. 0.00%, p &lt; .0001) and POLQ (2.40% vs. 0.00%, p &lt; .0001). Enrichment analysis further revealed LoF mutations unique to MTAP -loss samples were significantly enriched in the DDR pathway ( p &lt; .0001). For top germline pathogenic mutations, two DDR genes, RECQL4 (0.80% vs. 0.38%, p = 0.29) and BRCA2 (0.40% vs. 0.43%, p = 1), showed no significant differences between MTAP -loss and MTAP -intact samples. Conclusions: Potential association exists between MTAP loss and DDR pathway dysregulation, which may impact tumorigenic processes and therapeutic vulnerabilities. The enrichment of DDR-related LoF mutations indicates MTAP loss could exacerbate genomic instability by impairing DNA damage repair mechanisms, thereby increasing TMB and driving cancer progression with a distinct molecular profile. These vulnerabilities are primarily driven by somatic mutations, providing a rationale for exploring personalized treatment strategies.