Splicing mutation analysis reveals previously unrecognized pathways in lymph node-invasive breast cancer

Area of Science:

• Genomics
• Oncology
• Molecular Biology

Background:

• Large-scale breast cancer (BC) sequencing studies predominantly focus on protein-coding mutations.
• Analysis of mRNA splicing mutations in cancer remains limited, despite their significance in genetic disorders.

Purpose of the Study:

• To predict and validate splicing mutations in breast cancer exomes.
• To investigate the clinical relevance of identified splicing mutations, particularly in relation to lymph node metastasis.

Main Methods:

• Prediction of splicing mutations in 442 breast cancer tumor and matched normal exomes from The Cancer Genome Atlas (TCGA).
• Validation of predicted splicing defects through abnormal gene expression analysis.
• Pathway enrichment analysis of mutated genes.

Main Results:

• Identified 5,206 putative splicing mutations, with 988 confirmed cases including exon skipping, leaky, or cryptic splicing.
• Mutations in 9 NCAM1-related pathways were significantly elevated in tumors with lymph node metastasis compared to lymph node-negative tumors.

Conclusions:

• Comprehensive DNA sequencing data reporting should incorporate detailed splicing mutation analyses.
• Identifying deleterious splicing mutations can uncover novel mutated pathways relevant to genetic disorders and cancer progression.