Abstract 3461: Expression levels of TOX3 and the risk allele of the associated SNP rs3803662 predict adverse outcome for breast cancer patients.
Authors: Gudmundsdottir Eydis Th. , Barkardottir Rosa B. , Arason Adalgeir , Gunnarsson Haukur , Amundadottir Laufey Th. , Agnarsson Bjarni A. , Johannsson Oskar Th. , Reynisdottir Inga 
Published: August 2014

Abstract
Breast cancer is the most common cancer in women. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that increase the risk of breast cancer. The minor allele of SNP rs3803662 has been shown to correlate with increased breast cancer risk in women of European descent as well as with lower expression of TOX3. The SNP is located on chromosome 16q12.1 approximately 4 kb upstream of the gene. The aim of the study was to examine the association of the risk allele with the expression of TOX3 as well as the correlation of the mRNA levels and genotype with clinical and pathological characteristics. The SNP was genotyped in normal DNA from 160 breast cancer patients. The mRNA levels were measured in breast tumors by gene expression microarrays and confirmed by quantitative real-time (qRT)-PCR. The clinical and tumor characteristics were retrieved from hospital records and their association with the level of mRNA and the SNP was analyzed. Statistical and survival analyses were performed in R. The association of the risk allele of rs3803662 with lower TOX3 expression was confirmed in estrogen receptor (ER) positive tumors. It was more often observed in lobular than ductal tumors (p = 0.04), and carriers of the risk allele who had been diagnosed with luminal A tumors had shorter overall survival than carriers of the non-risk allele (p = 0.009). Correlation analysis with tumor histopathology showed that low TOX3 mRNA levels correlated with high Ki67 levels (p = 0.026) and tumors of the basal subtype (p &lt; 0.001), whereas high expression correlated with ER (p = 0.004) and progesterone receptor (p = 0.005) positivity. In addition, high TOX3 mRNA levels correlated with positive lymph nodes at time of diagnosis (p &lt; 0.001). Patients with ER positive tumors and high levels of TOX3 mRNA had shorter overall- and distant metastasis free-survival (p = 0.017 and p = 0.021, respectively), an effect that was mostly attributable to patients with tumors of the luminal B subtype. In conclusion, the results suggest that the risk allele of rs3803662 has the strongest effect in patients with tumors of the luminal A subtype. They also imply that the expression levels of TOX3 affect the progression of breast cancer but the effect may depend on the subtype.
Citation Format: Eydis Th. Gudmundsdottir, Rosa B. Barkardottir, Adalgeir Arason, Haukur Gunnarsson, Laufey Th. Amundadottir, Bjarni A. Agnarsson, Oskar Th. Johannsson, Inga Reynisdottir. Expression levels of TOX3 and the risk allele of the associated SNP rs3803662 predict adverse outcome for breast cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3461. doi:10.1158/1538-7445.AM2013-3461