Journal
SCIENTIFIC REPORTS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/srep07063
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Funding
- Canadian Breast Cancer Foundation
- Canadian Foundation for Innovation
- Canada Research Chairs Secretariat
- Natural Sciences and Engineering Research Council of Canada (NSERC) [371758-2009]
- Ontario Graduate Scholarship Program
- Pamela Greenaway-Kohlmeier Translational Breast Cancer Research Unit
- CIHR Strategic Training Program in Cancer Research and Technology Transfer
- University of Western Ontario
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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.
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