Xiujuan Wu, Lin Ren, Li Peng, Xuanni Tan, Wenting Yan, Xiaowei Qi, Yan Wang, Yi Zhang
The fatty acid metabolism model predicts survival and immune status; CD36 links lipid metabolism to tumor‑immune regulation. CD36‑associated immune phenotypes are associated with genomic alteration context, supporting a mutation‑TIME framework, while germline findings indicate that common germline variants regulating CD36 do not measurably influence breast cancer risk, suggesting the CD36 axis operates primarily through tumor-context-dependent mechanisms.
BACKGROUND: Fatty acid metabolism influences breast cancer prognosis and immune surveillance, but interactions with somatic mutations, the tumor immune microenvironment (TIME), and germline variation remain unclear.
METHODS: Using TCGA and GEO cohorts, we constructed a fatty acid metabolism‑related prognostic model usingdifferential expression, univariate Cox, and least absolute shrinkage and selection operator (LASSO)regression. Performance, immune infiltration, drug sensitivity, and CD36 function were evaluated in public data and MDA‑MB‑231 cells. Mutation‑TIME links were examined in a cBioPortal‑processed TCGA‑BRCA cohort with matched mRNA, somatic mutations, TMB, FGA, driver alterations, and TIME marker scores. Germline cis‑eQTL SNPs for signature genes and CD36 were tested against BCAC GWAS summary statistics.
RESULTS: The model stratified prognosis (high‑risk: OS HR = 2.15, 95%CI:1.68-2.75, P < 0.001; independent factor). High‑risk tumors showed immunosuppressive TIME and altered drug sensitivity. CD36 overexpression suppressed malignancy and modulated lipid/immune molecules. In 994 mutation‑annotated tumors, CD36‑high (n = 497) had lower fraction genome altered (FGA)than CD36‑low (median 0.221 vs. 0.328, FDR = 7.45 × 10⁻⁹), similar tumor mutation burden (TMB)(1.37 vs. 1.43, FDR = 0.294), and higher cytotoxic T‑cell, immune checkpoint, and suppressive myeloid/Treg scores. Recurrent PIK3CA/TP53 alterations and co‑mutation/mutual‑exclusivity patterns contextualized CD36‑TIME heterogeneity. Germline cis‑eQTLs for signature genes and CD36 showed no robust association with breast cancer risk, and CD36 was null across subtypes.
CONCLUSION: The fatty acid metabolism model predicts survival and immune status; CD36 links lipid metabolism to tumor‑immune regulation. CD36‑associated immune phenotypes are associated with genomic alteration context, supporting a mutation‑TIME framework, while germline findings indicate that common germline variants regulating CD36 do not measurably influence breast cancer risk, suggesting the CD36 axis operates primarily through tumor-context-dependent mechanisms.