Association of single nucleotide polymorphisms in Wnt signaling pathway genes with breast cancer in Saudi patients

PLoS One. 2013;8(3):e59555. doi: 10.1371/journal.pone.0059555. Epub 2013 Mar 14.

Abstract

Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni's correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Axin Protein / genetics
  • Breast Neoplasms / genetics*
  • Female
  • Genotype
  • Glycoproteins / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics*
  • Saudi Arabia
  • Transcription Factor 7-Like 2 Protein / genetics
  • Wnt Signaling Pathway / genetics
  • Wnt Signaling Pathway / physiology*
  • beta Catenin / genetics

Substances

  • AXIN2 protein, human
  • Axin Protein
  • DKK4 protein, human
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Transcription Factor 7-Like 2 Protein
  • WD repeat containing planar cell polarity effector
  • beta Catenin

Grants and funding

This study was financially supported by a grant from National Science, Technology and Innovation Plan strategic technologies program number 10-BIO897-2 in the Kingdom. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.