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.
Highlights
Breast cancer is a major health concern worldwide and is a leading cause of cancer related death in women [1]
Due to the relevance of Wnt signaling pathway in the pathogenesis of several different malignancies including breast cancers, we selected 15 single nucleotide polymorphisms (SNPs) in eight genes involved in this pathway to assess the association of genetic variation in these genes with risk of breast cancer in Saudi females (Table 1)
We observed statistically significant association of SNPs in bcatenin, AXIN2, DKK3, SFRP3 and TCF7L2 genes with breast cancer risk. Of these five SNPs, only SFRP3 SNP rs7775 was in the exonic region that codes for either arginine (Arg) or glycine (Gly) amino acid and was highly significant even after Bonferroni’s correction
Summary
Breast cancer is a major health concern worldwide and is a leading cause of cancer related death in women [1]. The age-standardized incidence rate for breast cancers in Saudi Arabia is 3.4 fold lower compared to United States, the median age of onset is 47 years, significantly lower than 62 years observed in patients from United States [1,2,3]. Recent studies have indicated breast cancer to be a heterogeneous disease that includes several molecular subtypes based on gene expression pattern [4,5]. Apart from genetic events leading to the initiation and progression of the disease earlier studies have shown an association of single nucleotide polymorphisms (SNPs) in different genes with an increased risk of breast cancer in different populations [9,10,11]. Despite advances in the treatment resulting in a trend towards better overall survival of the patient, the complete molecular basis of transformation is still unknown
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