A Comprehensive Mutational and Histopathological Analysis of STK11-Mutant Non–Small Cell Lung Carcinomas

Despite recent advances in the understanding of genomic and immunopathological mechanisms of lung cancer, this disease remains the leading cause of cancer-related deaths in the United States. STK11 (LKB1) mutations are present in approximately 20% of non-small cell lung cancers (NSCLCs) and drive tumor progression through disruption of cellular metabolism, polarity, and stress responses, ultimately leading to immune evasion and resistance to cancer therapy. Although these tumors are associated with poor prognoses, the clinicopathological significance of different STK11 mutation subtypes and their associations with tumor histology, cellular behavior, metastatic potential, and clinical outcomes remain incompletely understood. In this study, we retrospectively analyzed a large cohort of STK11-mutant and STK11 wild-type NSCLCs using a combination of next-generation sequencing, immunologic biomarkers, histopathological characterization, and radiographic imaging. Overall, we demonstrate that STK11-mutant tumors display diverse molecular and morphologic features and are associated with high rates of aggressive histopathological growth patterns, lymphovascular invasion, and spread through the airspaces. Among stage 4 cases, STK11 mutations had notable differences in organotropism, with the STK11-loss cohort in particular demonstrating the highest rates of brain metastases at the time of initial diagnosis. Furthermore, among stage 4 cases, whereas all STK11 mutation types resulted in decreased overall survival probability compared with the STK11 wild-type cohort, the effect appeared most pronounced among the STK11-loss/KRAS-mutant group. These findings underscore the heterogeneity of STK11-mutant NSCLCs and highlight the opportunity for further investigation into specific STK11 mutation subtypes in guiding prognosis and therapeutic decision-making for individuals with lung cancer.