Rare case of Pediatric Male Secretory Breast Carcinoma: An Integrative study with Genomic and Transcriptomic analysis

BackgroundMale breast cancer constitutes <1% of all breast cancer cases and is exceedingly rare in children, with pediatric male secretory breast carcinoma (SBC) reported only as isolated case reports. SBC is typically triple-negative and indolent, driven by the characteristic ETV6-NTRK3 fusion. However, the molecular landscape of aggressive pediatric male SBC remains poorly understood. ObjectivesTo characterise the genomic and transcriptomic features of a rare pediatric male case of SBC and identify clinically actionable molecular alterations using integrated next-generation sequencing. MethodsRetrospective fresh frozen tumour material underwent RNA and DNA extraction followed by whole-exome sequencing (WES) and transcriptome profiling using Illumina HiSeq X (150 bp paired-end). RNA-seq data were analysed using fastp, STAR, STAR-Fusion, and DESeq2. Mutational annotation was performed with COSMIC. Expression profiles were compared with ERBB2-stratified male breast cancers from TCGA-BRCA. Immune checkpoint and fusion interactome analyses were conducted to identify activated pathways. No formal statistical testing was performed due to the single-patient nature of the study. ResultsWES identified fifteen somatic exonic mutations, including recurrent alterations in ACAD11, PTPRM, INSR, and OR6A2, implicating pathways involved in metabolism, cell adhesion, signalling, and inflammatory responses. Transcriptomic profiling revealed high expression of secretory lineage genes (SCGB2A2, SCGB1D2), stress-response mediators (FTH1, CLU, S100A9), and biosynthetic markers (ribosomal proteins, TMSB4X). Hormone receptors (ESR1, PGR, AR) were negligible, whereas ERBB2 exhibited appreciable expression, suggesting a HER2-enriched subtype atypical for SBC. Immune checkpoint analysis showed elevated HMGB1, LAG3, LGALS9, PD-L1, and CD86 expression. Fusion analysis identified the canonical ETV6-NTRK3 rearrangement with validated breakpoints and evidence of MAPK/ERK and PI3K/AKT pathway activation. HER2 overexpression in this post-treatment sample may be attributable to gemcitabine-induced NF-{kappa}B activation or initial false-negative IHC. ConclusionThis integrative genomic-transcriptomic analysis uncovered multiple clinically actionable alterations in a rare pediatric male SBC, including HER2 expression and ETV6-NTRK3 fusion. These findings demonstrate the diagnostic and therapeutic value of comprehensive NGS in rare, aggressive paediatric tumours and highlight its potential to guide precision oncology. Early incorporation of transcriptomic profiling into diagnostic pathways may substantially improve treatment opportunities, particularly in resource-limited settings.