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Molecular differences between poorly and well/moderately differentiated lung adenocarcinoma and their clinical
Yi Shi1, Fangfang Chen1, Yuanyuan Weng1
1Department of Molecular Pathology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
Background:
Diagnostic and therapeutic techniques for lung adenocarcinoma (LUAD) have advanced rapidly. However, the morphology-based assessment of tumor differentiation commonly used in clinical practice has several limitations, including strong subjectivity, inability to reflect tumor heterogeneity, and limited prognostic predictive value. This study aimed to identify key genetic mutations associated with tumor differentiation features and explored their potential clinical impact of these molecular features on tumor prognosis and therapeutic response.
Methods:
In this study, 196 LUAD tissue samples collected from Fujian Cancer Hospital between 2021 and 2023 were analyzed using integrated high-throughput sequencing and comprehensive bioinformatics approaches. Molecular differences between poorly differentiated tumors and moderately/well-differentiated tumors were characterized. The effects of these molecular alterations on tumor behavior and therapeutic response were examined, with the aim of exploring biomarkers associated with poor prognosis and treatment in LUAD.
Results:
Our findings showed a significant quantitative difference in tumor mutation burden, EGFR co-mutations, patterns of co-occurrence resulting in distinct clinical outcomes. Among these alterations, mutations in LRP1B and TP53, as well as EGFR amplification, MET amplification, JAK2 deletion and CDKN2B deletion were significantly enriched in the poorly differentiated group, whereas EGFR mutations were significantly enriched in the moderately/well-differentiated group. We also identified MET amplification and LRP1B mutation as independent poor prognostic factors in LUAD. Moreover, a subset of poorly differentiated group exhibited DNA double-strand breaks possibly due to homologous recombination deficiency (HRD), along with frequent alterations of immune evasion-related genes.
Conclusions:
These findings provide novel insights into the molecular basis of LUAD and the development of novel targeted differentiation-related therapies and precision genome-guided treatments.