B21-06 A Novel Therapeutic Target for Lung Squamous Cell Carcinoma: Uncovering the Role of Somatic Repeat Expansions in Ptprz1 Regulation

Rationale Lung squamous cell carcinoma (LUSC) remains a significant cause of cancer mortality with limited therapeutic options. While genomic alterations in LUSC are well-documented, structural variations like large-scale somatic insertions have been underexplored. These alterations, especially somatic repeat expansions, could play a pivotal role in tumor progression. Nanopore long-read sequencing provides a unique opportunity to detect and characterize these elusive genetic changes, which could reveal novel therapeutic targets for LUSC. Our study aims to identify somatic repeat expansions and their impact on gene regulation, with a particular focus on PTPRZ1 (protein tyrosine phosphatase receptor type Z1), a potential oncogene. Methods We sequenced the genomes of 264 primary NSCLC tumor samples, including 113 LUSC and 151 lung adenocarcinoma (LUAD) cases, using nanopore sequencing technology. Paired blood samples were also analyzed to identify somatic insertions (≥50 bp). A comprehensive bioinformatics pipeline was developed to detect somatic repeat expansions, tandem duplications (TDs), and transposable element insertions (TEIs). To validate the functional significance of these insertions, we conducted targeted PCR, RNA sequencing, and chromatin conformation capture assays to confirm gene regulatory interactions. Results We identified a novel somatic simple repeat expansion (SRE) specifically enriched in LUSC tumors (40% of LUSC vs. 1% of LUAD). This SRE, located between distal enhancers, was found to regulate the expression of PTPRZ1, a gene involved in cellular signaling and cancer progression. Functional assays, including luciferase reporter assays and chromatin interaction studies, revealed that the SRE facilitated enhanced PTPRZ1 expression by enabling distal enhancer-promoter interactions. Inhibition of PTPRZ1 in LUSC cell lines with the somatic SRE significantly impaired tumor cell migration and proliferation, indicating that PTPRZ1 plays a crucial role in maintaining the aggressive phenotype of LUSC. Conclusion Our findings uncover a novel therapeutic target for LUSC: somatic repeat expansions regulating PTPRZ1 expression. This discovery offers new insights into the molecular mechanisms underlying LUSC and highlights the potential of targeting the PTPRZ1 pathway for therapeutic intervention. The ability of nanopore sequencing to detect these complex genomic alterations opens up new avenues for personalized cancer therapies and provides a foundation for future clinical trials aimed at inhibiting PTPRZ1 in LUSC patients. This abstract is funded by: None