LYN Mutations in Breast Cancer: Association with Central Nervous System Metastasis and Domain-Level Insights

Objectives: Central nervous system (CNS) metastasis is a major driver of morbidity in metastatic breast cancer, yet the molecular determinants of CNS tropism remain incompletely defined. LYN , a Src-family kinase integrating receptor tyrosine kinase and integrin signaling, is a biologically plausible mediator of metastatic traits. Design: We performed a retrospective, multi-study analysis of publicly available breast cancer cohorts aggregated in cBioPortal. After harmonization and de-duplication, LYN status was determinable in 5,947 invasive carcinoma of no special type (NST) tumors across 29 studies. The primary endpoint was CNS metastasis at any time (Yes/No), harmonized via a prespecified controlled vocabulary (case-insensitive substring mapping). Somatic LYN variants (coding SNVs/indels) were collapsed to patient-level classes (missense-only; truncating if any nonsense/frameshift/splice). Variants with resolvable positions were mapped to Src-family modules (SH4/Unique, SH3, SH2, SH2–kinase linker, kinase). Two-group comparisons used two-sided Fisher’s exact tests with exact 95% CIs; domain screens used omnibus χ² and Benjamini–Hochberg FDR control. A prespecified Firth logistic model evaluated truncating vs missense within LYN -mutant tumors. Setting: Public cancer genomics repositories (cBioPortal); multi-institutional cohorts. Participants: 5,947 tumors across multi-study cohorts with LYN status available. Interventions: None. Main outcome measures: Primary: ever-CNS metastasis (yes/no). Secondary: distribution of LYN variant classes and domains (SH4/Unique, SH3, SH2, linker, kinase). Results: CNS metastasis occurred in 5/46 (10.9%) LYN -mutated tumors vs 110/5,901 (1.9%) LYN wild-type tumors (OR = 6.42; 95% CI, 2.49–16.56; p = 0.0018). Within LYN -mutant cases, domain distributions differed by CNS status (omnibus χ² p ≈ 0.014); a one-versus-rest signal at the SH4/Unique N-terminus was nominally significant and borderline after FDR (unadjusted p ≈ 0.010; q ≈ 0.052; small in-domain n = 3). By mutation class, truncating vs missense showed a higher CNS-positive proportion (28.6% vs 7.9%) but did not reach significance (Fisher p = 0.166; alternatively framed OR = 4.22; exact 95% CI, 0.58–30.75; p = 0.182). Firth estimates were directionally consistent with wide profile CIs under sparse counts. Conclusions: Across pooled cohorts, LYN mutation is associated with increased odds of CNS metastasis, and domain context appears informative, with a small-sample, FDR-borderline enrichment at the SH4/Unique N-terminus. The truncating-class signal is exploratory given limited power. These data prioritize domain-aware LYN annotation for independent validation and mechanistic follow-up focused on membrane targeting, endothelial adhesion, and blood–brain barrier traversal. Trial registration: Not applicable.