Characterizing neurofibromin 1-altered breast cancer through genomic, functional, and clinical analyses

Breast cancer is a leading cause of cancer-related morbidity and mortality among women worldwide, with increasing incidence in China. The neurofibromatosis type 1 (NF1) gene, a critical tumor suppressor regulating the Ras/MAPK pathway, has been implicated in aggressive breast cancer phenotypes, yet its somatic alterations in Asian populations remain poorly characterized. This study integrates genomic, transcriptomic, and clinicopathological data from a Chinese breast cancer cohort (GDPH, n = 680), The Cancer Genome Atlas (TCGA), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) consortium to elucidate the role of NF1 in breast cancer. We identified somatic NF1 alterations in 5.9% of the GDPH cohort, with truncating mutations (41.03%) and co-occurring TP53 (72.5%) and PIK3CA (55.0%) mutations being predominant. Comparative analysis revealed ethnic variations, with higher NF1 mutation frequencies in the GDPH cohort (5.00%) compared to TCGA (2.80%) and METABRIC (3.75%). NF1-altered tumors exhibited elevated tumor mutational burden (TMB) and distinct co-alterations in DNA repair and chromatin remodeling pathways. Survival analysis indicated worse outcomes in NF1-mutated METABRIC patients (HR = 0.747, p = 0.0165). Functional enrichment analysis linked NF1 deficiency to metabolic reprogramming, immune dysregulation, and T-cell dysfunction, supported by murine models showing resistance to anti-PD-1 therapy upon NF1 knockdown. Our findings highlight NF1 as a key modulator of breast cancer progression, immune evasion, and therapeutic response, with implications for precision oncology in diverse populations. This study comprehensively characterizes somatic NF1 alterations and identifies potential therapeutic vulnerabilities in NF1-deficient breast cancers.