Translational Analysis of NSD3 Gene Amplification in Lung Squamous Cell Carcinoma: Clinical and Prognostic Insights From Histopathologic Analysis of Patient Samples.

INTRODUCTION

Nuclear receptor-binding SET domain 3 (NSD3) has been implicated as a driver of lung squamous cell carcinoma (LUSC) in preclinical studies. However, its clinicopathologic characteristics and prognostic significance remain unclear. To address this, we performed a histopathologic analysis of patient tissues.

METHODS

The NSD3 gene copy number was evaluated using fluorescence in situ hybridization in multiple cohorts of surgically resected LUSC cases, categorized into the amplification (Amp) or diploidy (Diploidy) groups. Clinicopathologic characteristics were compared, and artificial intelligence-based histopathologic image analysis evaluated the associations between NSD3 amplification, its protein expression, and cancer cell proliferation activity.

RESULTS

In the original cohort, NSD3 amplification was detected in 106 patients (39.6%). NSD3 protein expression was positively correlated with the NSD3 gene copy number (r = 0.528, p < 0.001). The Amp group exhibited higher mitotic counts (18 versus 13, p = 0.004) and Ki-67 index (18.5% versus 13.6%, p = 0.009) than the Diploidy group. The Amp group had shorter overall survival than the Diploidy group (110.6 versus 125.3 mo, p = 0.030), and multivariable analysis identified NSD3 amplification as an independent poor prognostic factor (hazard ratio = 1.59, p = 0.049). Furthermore, validation cohort analyses demonstrated consistent associations of NSD3 gene amplification with protein expression and cell proliferation, with comparable hazard ratios in prognostic evaluation.

CONCLUSIONS

Our study highlights the clinical relevance of NSD3 amplification in LUSC through analyses of patient tissues. These findings emphasize the potential of NSD3 as a prognostic biomarker and therapeutic target, bridging the gap between preclinical research and clinical application.