Integrated multi-omics profiling of pulmonary signet ring cell adenocarcinoma to reveal diagnostic markers, immune subtypes, and therapeutic vulnerabilities.

e20026 Background: Pulmonary signet ring cell adenocarcinoma (PSRCA) is a rare, aggressive subset of lung adenocarcinoma with a dismal prognosis. Its molecular characteristics remain poorly defined, leading to a lack of specific biomarkers and evidence-based therapeutic strategies. Methods: We conducted an integrated multi-omics analysis on formalin-fixed paraffin-embedded tumor samples from 39 treatment-naïve Chinese PSRCA patients—the largest cohort reported to date. Analyses included whole exome sequencing (WES), RNA sequencing (RNA-seq), and multiplex immunohistochemistry (mIHC) for deep profiling of the tumor immune microenvironment (TIME). Genomic alterations, transcriptomic signatures, and immune cell compositions were characterized. Differentially expressed genes (DEGs) were identified using edgeR and Mann-Whitney U test. TIME phenotypes were derived via unsupervised clustering of mIHC data. Results: WES revealed recurrent mutations in mucin family genes and distinct genome-wide copy number alterations. Transcriptomic analysis identified 121 uniquely downregulated and 94 uniquely upregulated genes in PSRCA. From these, five novel diagnostic markers were validated, effectively distinguishing PSRCA from lung adenocarcinoma, squamous cell carcinoma, and gastric signet ring cell carcinoma. TIME analysis classified tumors into three phenotypes: “Inflamed” (immune-hot), “Desert” (immune-cold), and “Hybrid”. The Inflamed phenotype showed a trend toward better response to anti-PD-1 therapy. Notably, EML4::ALK fusions were detected in 34.78% of patients with fusion data. All three ALK-fusion positive patients with the Hybrid TIME phenotype exhibited marked radiological responses to tyrosine kinase inhibitors (TKIs: crizotinib, lorlatinib, alectinib). Conclusions: This first comprehensive multi-omics study of PSRCA defines its distinct molecular landscape, proposes novel diagnostic biomarkers, and establishes a clinically relevant immune subtyping framework. The high frequency of ALK fusions and their association with TKI response in Hybrid TIME tumors provide a strong rationale for routine molecular profiling and precision therapy in this aggressive malignancy. Clinical trial information: NCT07207278 .