Disease associations of FGFR2, TNRC9 and MAP3K1 polymorphisms in breast cancer


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Amy Martin1, Lee Jordan2, Colin Purdie2, Alison Ashfield1, Lee Baker1, Philip R. Quinlan1, Fiona Carr1, Roger Tavendale1, Colin N.A. Palmer1, Alastair Thompson1, Jonathan Berg1

1University of Dundee, Dundee, UK, 2Ninewells Hospital and Medical School, Dundee, UK

Abstract

Background

Recent Genome Wide association studies have identified polymorphisms within/or near to Fibroblast Growth Factor Receptor Type 2 (FGFR2), Trinucleotide Repeat Containing 9 (TNRC9) and Mitogen Activated Protein Kinase Kinase Kinase 1 (MAP3K1) as markers of breast cancer susceptibility.

Method

A cohort of 340 cases and 379 controls was genotyped for the single nucleotide polymorphisms rs2981582 (FGFR2), rs3803662 (TNRC9) and rs889312 (MAP3K1), using Taqman based allelic discrimination assays (Applied Biosystems). We compared allele frequencies between cases and controls, and subsequently genotype with clinical and pathological features within the case cohort.

Results

An association between breast cancer and both FGFR2 (χ2=13.4, p=0.0012) and TNRC9 (χ2=14.3, p=0.0008) was confirmed, but there was no significant association with MAP3K1 (χ2=1.05, p=0.59). For FGFR2 and TNRC9 the polymorphisms appeared to act in a co-dominant (additive) fashion, with cancer risk increasing with the number of risk alleles (FGFR2 heterozygotes OR 1.28, 95%CI 084-1.95, FGFR2 homozygotes for the risk allele, OR 2.04, 95%CI 1.29-3.22, TNRC9 heterozygotes OR 1.26, 95%CI 0.75-2.13, homozygotes OR 2.12, 95%CI 1.27-3.53). There was no correlation between genotype and tumour grade, oestrogen receptor or HER2 status. There were associations between the FGFR2 risk allele and progesterone receptor negativity (p=0.003), the TNRC9 risk allele and node negativity (p=0.011), and between MAP3K1 and node positivity (p=0.015). Kaplan Meier Analysis did not show any correlation between survival and genotype for any of the genes.

Conclusions

Polymorphisms in TNRC9 and FGFR2 are significant genetic risk factors for breast cancer with a number of significant clinical correlates.

Background

Recent Genome Wide association studies have identified polymorphisms within/or near to Fibroblast Growth Factor Receptor Type 2 (FGFR2), Trinucleotide Repeat Containing 9 (TNRC9) and Mitogen Activated Protein Kinase Kinase Kinase 1 (MAP3K1) as markers of breast cancer susceptibility.

Method

A cohort of 340 cases and 379 controls was genotyped for the single nucleotide polymorphisms rs2981582 (FGFR2), rs3803662 (TNRC9) and rs889312 (MAP3K1), using Taqman based allelic discrimination assays (Applied Biosystems). We compared allele frequencies between cases and controls, and subsequently genotype with clinical and pathological features within the case cohort.

Results

An association between breast cancer and both FGFR2 (χ2=13.4, p=0.0012) and TNRC9 (χ2=14.3, p=0.0008) was confirmed, but there was no significant association with MAP3K1 (χ2=1.05, p=0.59). For FGFR2 and TNRC9 the polymorphisms appeared to act in a co-dominant (additive) fashion, with cancer risk increasing with the number of risk alleles (FGFR2 heterozygotes OR 1.28, 95%CI 084-1.95, FGFR2 homozygotes for the risk allele, OR 2.04, 95%CI 1.29-3.22, TNRC9 heterozygotes OR 1.26, 95%CI 0.75-2.13, homozygotes OR 2.12, 95%CI 1.27-3.53). There was no correlation between genotype and tumour grade, oestrogen receptor or HER2 status. There were associations between the FGFR2 risk allele and progesterone receptor negativity (p=0.003), the TNRC9 risk allele and node negativity (p=0.011), and between MAP3K1 and node positivity (p=0.015). Kaplan Meier Analysis did not show any correlation between survival and genotype for any of the genes.

Conclusions

Polymorphisms in TNRC9 and FGFR2 are significant genetic risk factors for breast cancer with a number of significant clinical correlates.