Genomic and transcriptomic landscape of overweight Chinese breast cancer reveals NOTCH2 mutation–mediated endocrine resistance and therapeutic strategies

Vollständiger Abstract

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Abstract Background Obesity (OB) and overweight (OW) are common in patients with breast cancer and are associated with inferior outcomes, yet their impact on tumor molecular architecture remains incompletely understood. This study aimed to define the genomic and transcriptomic features of breast cancer in OW/OB Chinese patients and to identify clinically relevant biomarkers and prognostic models for this population. Methods We performed targeted sequencing of matched tumor–blood samples from 3924 Chinese female patients with breast cancer to profile somatic and germline alterations, together with comprehensive clinicopathological annotation. In parallel, transcriptomic profiling was conducted in 236 tumors to characterize body mass index (BMI)-associated biological programs and explore potential therapeutic vulnerabilities. Results OW/OB status was associated with significantly worse survival, particularly in the hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR + /HER2 − ) subtype. In HR + /HER2 − tumors, OW/OB patients showed higher frequencies of FOXA1 and ALK somatic mutations and FANCA germline variants, whereas TP53 and ARID1A somatic alterations were more frequent in underweight/normal-weight patients. Among OW/OB cases, we identified 20 adverse prognostic mutations and developed a survival model with robust discriminatory performance. Notably, NOTCH2 mutation emerged as a key predictor of poor outcome in OW/OB patients, especially in the HR + /HER2 − subgroup. Transcriptomic analyses further demonstrated that NOTCH2 -mutant tumors exhibited signatures associated with impaired drug response and phospholipid efflux, along with reduced apoptosis-related programs, and were predicted to be less sensitive to tamoxifen and palbociclib, suggesting a potential endocrine-resistant phenotype. Conclusions This integrative multi-omics study reveals that elevated BMI is associated with distinct molecular features and unfavorable clinical outcomes in breast cancer, especially in HR + /HER2 − disease. Our findings identify NOTCH2 as a potential biomarker of endocrine resistance and provide a molecular basis for BMI-adapted prognostication and personalized therapeutic strategies in OW/OB breast cancer patients.