Lu He, Xianfeng Xu, Lingfeng Bi, Chen Ji, Zhiwen Li, Yating Fu, Meng Zhu, Cheng Wang, Guangfu Jin, Hongxia Ma, Weimin Li, Zhoufeng Wang, Na Qin, Dong Hang, Hongbing Shen
These findings provide a molecular framework for the IASLC grading spectrum and identify Grade 3 LUAD as a distinct instability-associated and dedifferentiated biological state.
BACKGROUND: The IASLC grading system has prognostic utility and potential therapeutic implications in invasive non-mucinous lung adenocarcinoma (LUAD), but the molecular basis underlying the grading spectrum remains unclear.
METHODS: We performed whole-genome sequencing in 138 Chinese patients with invasive non-mucinous LUAD and RNA sequencing of 96 matched tumor-normal tissue pairs to systematically characterize the molecular features across grades, including coding driver events, mutational signatures, non-coding regulatory disruptions, and transcriptional programs.
RESULTS: Compared with Grade 1-2 tumors, Grade 3 LUADs exhibited heightened invasive potential, manifested by more advanced stage, more frequent spread through air spaces, and independently worse survival. Grade 3 tumors had elevated tumor mutational burden and were enriched for alterations in genome maintenance and cell-cycle genes, including TP53, as well as genes implicated in DNA damage response, including ZFHX4. APOBEC-associated mutagenesis was selectively enriched in Grade 3 tumors independent of smoking status, consistent with an instability-associated phenotype. Recurrent non-coding regulatory disruptions affected lung lineage-defining genes, particularly surfactant-associated genes, and were correlated with reduced expression. Transcriptomic profiling revealed epithelial dedifferentiation, loss of pulmonary homeostatic programs, and activation of proliferative and stress-related pathways. Notably, MUC16 emerged as a convergent event linking genomic and transcriptional dysregulation, with coding mutations associated with higher expression and increased expression in Grade 3 tumors correlating with the proportion of high-grade histologic patterns.
CONCLUSIONS: These findings provide a molecular framework for the IASLC grading spectrum and identify Grade 3 LUAD as a distinct instability-associated and dedifferentiated biological state.