Identification of Poor Prognostic Markers in Triple-Negative Breast Cancer Using Whole Exome Sequencing.

PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype of breast cancer associated with poor clinical outcomes. Although programmed death ligand 1 (PD-L1) expression has emerged as both a prognostic and predictive biomarker, its utility remains limited, especially in PD-L1-negative tumors. The identification of additional molecular markers is crucial for improving prognostic stratification and guiding treatment strategies. METHODS: Formalin-fixed, paraffin-embedded tumor tissues from 38 patients with TNBC were analyzed. PD-L1 expression was assessed using immunohistochemistry and categorized as positive or negative. Whole-exome sequencing was performed, and somatic variants were analyzed using Maftools. Mutational signatures were compared with the Catalogue Of Somatic Mutations In Cancer reference profiles. Survival analyses were performed to evaluate the prognostic significance of the identified variants. RESULTS: Mutational landscape analysis revealed that C>T and G>A transitions were the most frequent base substitutions. PD-L1-negative tumors exhibited a predominance of single-base substitution (SBS) 5, whereas PD-L1-positive tumors resembled SBS6, reflecting potential differences in the underlying mutational processes. Comparative analysis identified 12 PD-L1-negative-specific and seven PD-L1-positive-specific variants. Among PD-L1-negative tumors, mutations in ANGPTL5 and KIAA1549L were significantly associated with worse overall survival. CONCLUSION: Our findings highlight distinct mutational profiles and prognostic variants according to PD-L1 status in TNBC. ANGPTL5 and KIAA1549L variants may serve as potential prognostic markers for PD-L1-negative tumors. These results underscore the value of incorporating genomic information to refine the prognostic stratification of TNBC.