GPC3: a novel mutated gene in pleuropulmonary blastoma.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a rare pediatric sarcoma often associated with DICER1 mutations. However, additional genetic factors may influence disease progression and prognosis. This study identifies a novel mutation in the GPC3 gene and evaluates its potential as a prognostic biomarker in PPB. METHODS: Whole-genome sequencing (WGS) was conducted on blood samples from a three-generation family with PPB. Candidate genes were prioritized based on autosomal recessive inheritance patterns and association with PPB. Immunohistochemistry was used to assess GPC3 expression in PPB tumor tissues, adjacent areas, and congenital pulmonary airway malformation (CPAM) samples. Kaplan-Meier survival analysis was performed, comparing survival outcomes in patients with varying levels of GPC3 expression. RESULTS: Seventeen candidate genes, including GPC3, were identified. A novel missense mutation in the GPC3 gene was confirmed, with significantly higher GPC3 expression observed in PPB tissues than in CPAM or adjacent non-tumor tissues. Survival analysis revealed that patients with high GPC3 expression (GPC3+++) exhibited a markedly lower two-year survival rate (30%) compared to moderate (GPC3++, 75%) and low (GPC3+, 90.9%) expression groups (p = 0.0035). The correlation between elevated GPC3 levels and poor prognosis suggests GPC3 as a potential biomarker for disease severity in PPB. CONCLUSION: Our findings propose GPC3 as a novel mutation contributing to PPB susceptibility and progression. Elevated GPC3 expression correlates with poorer survival outcomes, indicating its potential as a prognostic marker and therapeutic target in PPB management.