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The role of the fat mass and obesity associated gene (FTO) in breast cancer risk

Cancer Genetics Program, Division of Hematology/Oncology, Department of Medicine and Robert H, Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 676 N St Clair st suite 850, Chicago, IL 60611, USA.
BMC Medical Genetics (Impact Factor: 2.45). 04/2011; 12:52. DOI: 10.1186/1471-2350-12-52
Source: PubMed

ABSTRACT Obesity has been shown to increase breast cancer risk. FTO is a novel gene which has been identified through genome wide association studies (GWAS) to be related to obesity. Our objective was to evaluate tissue expression of FTO in breast and the role of FTO SNPs in predicting breast cancer risk.
We performed a case-control study of 354 breast cancer cases and 364 controls. This study was conducted at Northwestern University. We examined the role of single nucleotide polymorphisms (SNPs) of intron 1 of FTO in breast cancer risk. We genotyped cases and controls for four SNPs: rs7206790, rs8047395, rs9939609 and rs1477196. We also evaluated tissue expression of FTO in normal and malignant breast tissue.
We found that all SNPs were significantly associated with breast cancer risk with rs1477196 showing the strongest association. We showed that FTO is expressed both in normal and malignant breast tissue. We found that FTO genotypes provided powerful classifiers to predict breast cancer risk and a model with epistatic interactions further improved the prediction accuracy with a receiver operating characteristic (ROC) curves of 0.68.
In conclusion we have shown a significant expression of FTO in malignant and normal breast tissue and that FTO SNPs in intron 1 are significantly associated with breast cancer risk. Furthermore, these FTO SNPs are powerful classifiers in predicting breast cancer risk.

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    • "In selecting the genes and their SNPs we reviewed findings from GWAS and other independent studies and applied minor allele frequency filtering approach and function prediction method to select a total of 64 SNPs of eight genes (Frayling et al. 2007; Kakamani et al. 2011; Hunter et al. 2007; Dossus et al. 2008; Langsenlehner et al. 2006; Zhang et al. 2012; Healey et al. 2011; Dossus et al. 2010; Stacey et al. 2007; Andreasen et al. 2008; Rebbeck et al. 2009; Easton et al. 2007; Brasky et al. 2011) (Table 2). "
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    • "Brennan et al. demonstrated that FTO is associated with a risk for lung cancer using a Mendelian randomization approach [12]. The results from clinical pathology analysis showed that FTO is expressed in both normal and malignant breast tissue, and the SNPs are significantly associated with breast cancer risk [2]. In the present study, we cloned and analyzed the human FTO promoter to gain a better understanding of its transcriptional regulation. "
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    ABSTRACT: Fat mass and obesity associated gene (FTO) is the first gene associated with body mass index (BMI) and risk for diabetes. FTO is highly expressed in the brain and pancreas, and is involved in regulating dietary intake and energy expenditure. To investigate the transcriptional regulation of FTO expression, we created 5'-deletion constructs of the FTO promoter to determine which transcription factors are most relevant to FTO expression. The presence of an activation region at -201/+34 was confirmed by luciferase activity analysis. A potential Foxa2 (called HNF-3β) binding site and an upstream stimulatory factor (USF)-binding site was identified in the -100 bp fragment upstream of the transcription start site (TSS). Furthermore, using mutagenesis, we identified the Foxa2 binding sequence (-26/-14) as a negative regulatory element to the activity of the human FTO promoter. The USF binding site did not affect the FTO promoter activity. Chromatin immunoprecipitation (ChIP) assays were performed to confirm Foxa2 binding to the FTO promoter. Overexpression of Foxa2 in HEK 293 cells significantly down-regulated FTO promoter activity and expression. Conversely, knockdown of Foxa2 by siRNA significantly up-regulated FTO expression. These findings suggest that Foxa2 negatively regulates the basal transcription and expression of the human FTO gene.
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    Journal of biomolecular Structure & Dynamics 12/2011; 29(3):471-83. DOI:10.1080/07391102.2011.10507399 · 2.98 Impact Factor
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