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Open Access Research article

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 Gudmundsdottir1, Rosa B Barkardottir12, Adalgeir Arason12, Haukur Gunnarsson13, Laufey Th Amundadottir4, Bjarni A Agnarsson12, Oskar Th Johannsson25 and Inga Reynisdottir1*

Author affiliations

1 Department of Pathology, Landspitali-University Hospital, Hringbraut, 101, Reykjavik, Iceland

2 BMC, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101, Reykjavik, Iceland

3 Present address: Actavis, Hafnarfjordur, Iceland

4 Department of Health and Human Services, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

5 Department of Oncology, 20A, Landspitali-University Hospital, Hringbraut, 101, Reykjavik, Iceland

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Citation and License

BMC Cancer 2012, 12:621  doi:10.1186/1471-2407-12-621

Published: 27 December 2012

Abstract

Background

The 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.

Methods

The 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.

Results

An 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.

Conclusions

The 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.

Keywords:
TOX3; LOC643714; rs380662; Risk allele; Breast cancer; Clinical; Pathological; Survival; Oestrogen receptor