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

Sci Rep. 2014 Nov 14:4:7063. doi: 10.1038/srep07063.


Somatic mutations reported in large-scale breast cancer (BC) sequencing studies primarily consist of protein coding mutations. mRNA splicing mutation analyses have been limited in scope, despite their prevalence in Mendelian genetic disorders. We predicted splicing mutations in 442 BC tumour and matched normal exomes from The Cancer Genome Atlas Consortium (TCGA). These splicing defects were validated by abnormal expression changes in these tumours. Of the 5,206 putative mutations identified, exon skipping, leaky or cryptic splicing was confirmed for 988 variants. Pathway enrichment analysis of the mutated genes revealed mutations in 9 NCAM1-related pathways, which were significantly increased in samples with evidence of lymph node metastasis, but not in lymph node-negative tumours. We suggest that comprehensive reporting of DNA sequencing data should include non-trivial splicing analyses to avoid missing clinically-significant deleterious splicing mutations, which may reveal novel mutated pathways present in genetic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • CD56 Antigen / metabolism
  • Computational Biology
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • Databases, Nucleic Acid
  • Female
  • Gene Order
  • Genetic Loci
  • Humans
  • Lymph Nodes / pathology
  • Lymphatic Metastasis
  • Mutation*
  • Polymorphism, Single Nucleotide
  • RNA Splicing*
  • Reproducibility of Results
  • Signal Transduction*


  • CD56 Antigen
  • NCAM1 protein, human