Genomic Landscape of Resected Invasive Mucinous Adenocarcinoma of the Lung.

Abstract

Background: Invasive mucinous adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma, accounting for 3%-10% of cases. It is often associated with KRAS mutations or, in nonsmokers, NRG1 fusions. Approximately 20% of IMAs have unclear genomic backgrounds. This study aimed to clarify the genomic etiology of these cases through a retrospective molecular analysis and RNA sequencing.

Patients and methods: This study analyzed 107 cases of NSCLC that were treated by surgical resection at Aichi Cancer Center from 2009 to 2023, with a focus on IMAs. For cases with unclear genomic backgrounds, RNA sequencing was conducted to identify potential driver gene alterations, and the results were compared to those of known KRAS-positive cases. Statistical analyses, including Cox regression and Kaplan-Meier analyses, were used to evaluate risk factors, recurrence-free survival, and the prognosis.

Results: In this study, 107 cases of resected IMA were analyzed. KRAS mutations were found in 70.1% of cases, followed by NRG1 fusions (9.2%), and other mutations. A novel fusion gene, ATP6V1H::LYN, was discovered in 1 case. RNA sequencing and a gene set enrichment analysis revealed distinct molecular pathways in KRAS-positive tumors, including the activation of oxidative phosphorylation and TNFα-NF-κB signaling. Tumors with no driver gene alterations exhibited a higher frequency of copy number variations and tumor mutational burden than KRAS and NRG fusion-positive cases.

Conclusion: IMAs are characterized by relatively higher incidences of harboring KRAS mutations and NRG fusion genes, revealing potential therapeutic targets including druggable mutations and immune-related markers, while highlighting the heterogeneous genomic background and utility of RNA sequencing.