The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714 predict adverse outcome for breast cancer patients.

Eydis Th Gudmundsdottir,Oskar Th Johannsson,Rosa B Barkardottir,Inga Reynisdottir,Laufey Th Amundadottir,Bjarni A Agnarsson,Adalgeir Arason,Haukur Gunnarsson

doi:10.1186/1471-2407-12-621

Abstract

BackgroundThe minor allele of SNP rs3803662 has been shown to correlate with increased breast cancer risk and with lower expression of TOX3. The SNP is closely located to TOX3 residing within an uncharacterised gene LOC643714. The aim of the study was to examine the association of the risk allele with expression of TOX3 and LOC643714, and of mRNA levels and genotype with clinical and pathological characteristics.MethodsThe SNP was genotyped in DNA isolated from blood and normal tissue from 160 breast cancer patients and mRNA levels were measured by microarrays and quantitative real-time (qRT)-PCR in breast tumours. Association with clinical and pathological characteristics was analysed by parametric tests.ResultsAn association of the risk allele of rs3803662 with lower TOX3 expression was confirmed in oestrogen receptor (ER) positive tumours. It was more often observed in lobular tumours (p = 0.04), and carriers of the risk allele who had been diagnosed with luminal A tumours had shorter overall survival (OS) than carriers of the non-risk allele (p = 0.01). Positive correlation between the mRNA levels of TOX3 and LOC643714 was observed (r = 0.44 and p < 0.001). Association analysis with tumour pathology showed that low TOX3 and LOC643714 expression correlated with high Ki67 levels (p = 0.026 and p = 0.002) and the basal subtype (p < 0.001 and p < 0.001), whereas high expression correlated with ER (p = 0.004 and p < 0.001) and progesterone receptor (PgR) (p = 0.005 and p < 0.001) expression. Furthermore, high TOX3 and LOC643714 correlated with positive lymph nodes (p < 0.001 and p = 0.01). Patients with ER positive tumours and high levels of TOX3 mRNA had shorter overall- and distant metastasis free-survival (p = 0.017 and p = 0.021), an effect mostly attributable to patients with luminal B tumours.ConclusionsThe results suggest that the effect of the risk allele of rs3803662 is strongest in luminal A tumours and that the expression levels of TOX3 and/or LOC643714 affect the progression of breast cancer. The effect may vary depending on the subtype and developmental stage of the tumour.

Highlights

The minor allele of Single nucleotide polymorphism (SNP) rs3803662 has been shown to correlate with increased breast cancer risk and with lower expression of TOX3
The rs3803662 risk allele is associated with shorter overall survival (OS) Correlation analysis between the SNP genotypes and clinical and pathological factors of breast cancer was performed
When survival was analysed according to molecular subtypes, patients diagnosed with luminal A tumours who carried the risk allele had shorter OS as compared to patients homozygous for the non-risk allele (p = 0.01, Figure 1)

Summary

Introduction

The minor allele of SNP rs3803662 has been shown to correlate with increased breast cancer risk and with lower expression of TOX3. It was demonstrated that the minor allele of rs3803662 conferred increased risk of breast cancer in European women [5,6], a finding that has been validated in large studies of unselected patients and patients with a familial history of breast cancer and meta-analyses [7,8,9,10,11,12,13]. This finding was observed in women of East Asian descent [14,15,16] but not in women of African American descent [17,18,19]. The minor rs3803662 allele increased the risk of breast cancer in BRCA1 and BRCA2 carriers [21,23,24] as well as in a population-based study of men [25]

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