Multi‑omics analysis identifies different molecular subtypes with unique outcomes in early-stage poorly differentiated lung adenocarcinoma

Introduction: Early-stage poorly differentiated lung adenocarcinoma (LUAD) is plagued by a high risk of postoperative recurrence, and its prognostic heterogeneity complicates treatment and surveillance planning. We conducted this integrative multi-omics study to identify those patients with a truly high risk of adverse outcomes. Methods: Whole-exome, RNA and whole methylome sequencing were carried out on 101 treatment-naïve early-stage poorly differentiated LUADs. Integrated analyses were conducted to disclose molecular characteristics and explore molecular subtyping. Functional validation of key molecules was carried out through in vitro and in vivo experiments. Results: Recurrent tumors exhibited significantly higher ploidy (p = 0.024), the fraction of the genome altered (FGA, p = 0.042), and aneuploidy (p = 0.022) compared to non-recurrent tumors, as well as a higher frequency of CNVs. Additionally, recurrent tumors showed hypomethylation at both the global level and in CpG island regions. Integrative transcriptomic and methylation analyses identified three molecular subtypes (C1, C2, and C3), with the C1 subtype presenting the worst prognosis (p = 0.024). Although frequently mutated genes showed similar mutation frequencies across the three subtypes, the C1 subtype exhibited the highest tumor mutation burden (TMB), mutant-allele tumor heterogeneity (MATH), aneuploidy, and HLA loss of heterozygosity (HLA-LOH), along with relatively lower immune cell infiltration. Furthermore, GINS1 and CPT1C were found to promote LUAD progression, and their high expression correlated with a poor prognosis. Conclusions: This multi-omics study identified three integrative subtypes with distinct prognostic implications, paving the way for more precise management and postoperative monitoring of early-stage poorly differentiated LUAD.