Identification of significant single-nucleotide polymorphisms associated with breast cancer recurrence and metastasis using GWAS

Abstract

Background

Identification of risk genes and loci associated with the recurrence and metastasis of breast cancer (BC) is of utmost importance. Genome-wide association studies (GWASs) represent valuable tools for identifying the disease risk associated with a given single-nucleotide polymorphism (SNP); they offer significant insights into the disease progression mechanism by analyzing SNP information of the entire genome. Though GWAS has already identified several genetic susceptibility SNPs for BC, their significance in the recurrence and metastasis of this cancer remains unclear. Here, we used a GWAS approach to identify SNPs specifically associated with the risk of BC recurrence and metastasis.

Methods

This study adopted a two-stage GWAS approach. In the first stage, 97 pairs of BC patients with or without recurrence and metastasis, treated at the Shandong Cancer Hospital and Institute from November 2013 to April 2014, were identified using propensity score matching. DNA extracted from the patient peripheral blood was then subjected to Illumina ASA chip analysis for genome-wide SNP detection. In the second stage, the findings were verified in a validation set of 854 BC patients recruited at the same hospital from May 2014 to June 2015. SNP genotyping was performed using time-of-flight mass spectrometry. The SNP loci and their corresponding genes and pathways were analyzed using the DAVID (https://david.ncifcrf.gov/) online enrichment analysis tool.

Results

Based on the GWAS results, 191 SNP-related genes significantly associated with BC recurrence and metastasis were identified as expression quantitivative trait loci (p < 0.001). Functional and pathway enrichment analyses subsequently revealed the potential involvement of glutamatergic synaptic transmission, calcium signaling, and insulin secretion pathways in BC recurrence and metastasis. Based on genotype correlation and database expression levels, rs10108514, rs12920540, rs4273077, and rs4730155 were found to be significantly associated with the risk of BC recurrence and metastasis.

Conclusion

Our study suggests that the SNPs rs10108514, rs12920540, rs4273077, and rs4730155 are correlated with the risk of BC recurrence and metastasis, potentially by being implicated in glutamatergic synaptic transmission, calcium signaling, and insulin secretion pathways.