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PLoS One. 2014 Jun 2;9(6):e98229. doi: 10.1371/journal.pone.0098229. eCollection 2014.

Systematic pathway enrichment analysis of a genome-wide association study on breast cancer survival reveals an influence of genes involved in cell adhesion and calcium signaling on the patients' clinical outcome.

Author information

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Radiation Sciences & Oncology, Umeå University, Umeå, Sweden.
Cancer Research Laboratory, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
The Malmö Diet and Cancer Study, Lund University, Malmö, Sweden; Department of Plastic Surgery, Skåne University Hospital, Malmö, Lund University, Malmö, Sweden.
Department of Public Health and Clinical Medicine/Nutritional, Research, Umeå University, Umeå, Sweden.
Department of Radiation Sciences & Oncology, Umeå University, Umeå, Sweden; Cancer Center Stockholm Gotland, Stockholm, Sweden.
Institute of Human Genetics, Department of Genomics, University of Bonn, Bonn, Germany; Division of Medical Genetics and Department of Biomedicine, University of Basel, Basel, Switzerland.
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.


Genome-wide association studies (GWASs) may help to understand the effects of genetic polymorphisms on breast cancer (BC) progression and survival. However, they give only a focused view, which cannot capture the tremendous complexity of this disease. Therefore, we investigated data from a previously conducted GWAS on BC survival for enriched pathways by different enrichment analysis tools using the two main annotation databases Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The goal was to identify the functional categories (GO terms and KEGG pathways) that are consistently overrepresented in a statistically significant way in the list of genes generated from the single nucleotide polymorphism (SNP) data. The SNPs with allelic p-value cut-offs 0.005 and 0.01 were annotated to the genes by excluding or including a 20 kb up-and down-stream sequence of the genes and analyzed by six different tools. We identified eleven consistently enriched categories, the most significant ones relating to cell adhesion and calcium ion binding. Moreover, we investigated the similarity between our GWAS and the enrichment analyses of twelve published gene expression signatures for breast cancer prognosis. Five of them were commonly used and commercially available, five were based on different aspects of metastasis formation and two were developed from meta-analyses of published prognostic signatures. This comparison revealed similarities between our GWAS data and the general and the specific brain metastasis gene signatures as well as the Oncotype DX signature. As metastasis formation is a strong indicator of a patient's prognosis, this result reflects the survival aspect of the conducted GWAS and supports cell adhesion and calcium signaling as important pathways in cancer progression.

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