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

 

BMC Cancer 2012, 12:621.

Eydis Th. Gudmundsdottir1, Rosa B. Barkardottir1,2, Adalgeir Arason1,2, Haukur Gunnarsson1,3, Laufey Th. Amundadottir4, Bjarni A. Agnarsson1,2, Oskar Th. Johannsson2,5, Inga Reynisdottir1

1Department of Pathology and 5Department of Oncology, 20A, Landspitali-University Hospital, Hringbraut, 101 Reykjavik, Iceland; 2BMC, Faculty of Medicine, University of Iceland, Vatnsmyrarvegi 16, 101 Reykjavik, Iceland; 3Present address: Actavis, Hafnarfjordur, Iceland; 4Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

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.

PMID: 23270421

Inga Reynisdóttir-1High levels of TOX3 mRNA were associated with shorter overall survival.  Breast tumours were divided into high (35 tumours) and low (53 tumours) TOX3 expressing tumours based on the average expression in the ER positive breast tumour group.  Breast cancer patients who carried ER positive tumours that expressed high levels of TOX3 mRNA lived for fewer years after diagnosis of breast cancer than those carrying tumours that expressed low levels of TOX3 mRNA.  A slight modification of Figure 4c from Gudmundsdottir et al., BMC Cancer 2012, 12:621.

 

Explanation of findings:

Changes in single nucleotides in the human genome, termed single nucleotide polymorphisms (SNPs), are known to impart a risk of breast cancer.  In this study we analyzed whether the breast cancer risk SNP rs3803662, located on chromosome 16, or the mRNA product of two nearby genes, TOX3 and LOC643714, were associated with clinical and pathological characteristics that would indicate worse prognosis for breast cancer patients.  The results suggested that patients with luminal A tumours who carried two risk alleles of SNP rs3803662 lived for a shorter time period after diagnosis of breast cancer than patients who carried either one or two non-risk alleles.  Luminal A tumours are a subtype of breast tumours and with luminal B tumours they constitute the majority of tumours that express the oestrogen receptor (ER).  In ER positive tumours, the risk allele of SNP rs3803662 correlated with low level expression of TOX3 mRNA.   However, patients with ER positive tumours expressing low levels of TOX3 mRNA lived for a longer time (see Figure) after diagnosis than those with ER positive tumours that expressed high levels of TOX3 mRNA.  This effect was mostly attributable to luminal B tumours. Based on these results we suggested that SNP rs3803662 may affect TOX3 mRNA expression differently based on the tumour subtype with opposite effects in luminal A and luminal B tumours.  Further analysis is needed to test that hypothesis but from this study we conclude that the SNP and TOX3 mRNA level have an adverse effect on the prognosis of ER positive breast cancer patients.      

 

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