Article

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.

Download full-text

Full-text

Available from: Kui Zhang, Sep 02, 2014
0 Followers
 · 
146 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic internal inflammation secondary to adiposity is a risk factor for sporadic breast cancer and Post-Menopausal Breast Cancer (PMBC) is largely defined as such. Adiposity is one of the clinical criteria for the diagnosis of Metabolic Syndrome (MetS) and is a risk factor for PMBC. We examined SNPs of eight genes implicated in adiposity, inflammation and cell proliferation in a Prospective-specimen-collection, Retrospective-Blinded-Evaluation (PRoBE) design approach. A total of 180 cases and 732 age-matched controls were identified from the MyCode prospective biobank database and then linked to the Clinical Decision Information System, an enterprise-wide data warehouse, to retrieve clinico-demographic data. Samples were analyzed in a core laboratory where the personnel were masked to their status. Results from multivariate logistic regression yielded one SNP (rs2922126) in the GHSR as protective against PMBC among homozygotes for the minor allele (A/A) (OR = 0.4, 95% CI 0.18-.89, P-value = .02); homozygosity for the minor allele (C/C) of the SNP (rs889312) of the gene MAP3K1 was associated with the risk of PMBC (OR = 2.41, 95% CI 1.25-4.63 P-value = .008). Advanced age was protective against PMBC (OR = 0.98, 95% CI 0.95-0.99, P-value = .02). Family history of breast cancer (OR = 2.22, 95% CI 1.14-4.43. P = .02), HRT (OR = 3.35; 95% CI 2.15-5.21, P < .001), and MetS (OR = 14.83, 95% CI 5.63-39.08, P < .001) and interaction between HRT and MetS (OR = 39.38, 95% CI 15.71-98.70, P < .001) were associated with the risk of PMBC. We did not detected significant interactions between SNPs or between the SNPs and the clinico-demographic risk factors. Our study further confirms that MetS increases the risk of PMBC and argues in favor of reducing exposure to HRT. Our findings are another confirmation that low penetrance genes involved in the inflammatory pathway, i.e. MAP3KI gene, may have a plausible causative role in PMBC. Given the fact that genetic constitutionality of individuals cannot be changed, efforts should be focused on life style modification.
    SpringerPlus 11/2013; 2:638. DOI:10.1186/2193-1801-2-638
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Overweight and obesity are common health problems in modern society, particularly in developed countries. Excessive body mass has been linked to numerous diseases, such as cardiovascular diseases, diabetes, and cancer. Fat mass and obesity-associated protein (FTO) activity have direct impact on food intake and results in obesity. Inhibition of FTO activity may cause weight loss and reduce obese-linked health risks. We investigated the potential weight loss effects of traditional Chinese medicine (TCM), particularly by inhibiting FTO functions. Molecular docking was performed to screen TCM compounds from TCM Database@Taiwan (http://tcm.cmu.edu.tw). Three candidates were identified that contained either a tetrahydropyridine group or potent electronegative phenol group in the structure scaffold. Molecular dynamics simulation analysis of the docking poses of each complex indicated stabilizing trends in the protein-ligand complex movements. In addition, the number of hydrogen bonds increased throughout the 20 ns simulation. These results suggest that these TCM candidates could be potential FTO inhibitors through competitive inhibition.
    Journal of biomolecular Structure & Dynamics 12/2011; 29(3):471-83. DOI:10.1080/07391102.2011.10507399 · 2.98 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is generally acknowledged as a risk factor for endometrial cancer, as accumulated adipocytes partly contribute to the increased production of estrogen which is involved in dysregulated cell growth and metastasis in early endometrial carcinogenesis. Thus we evaluated in this study expression of the fat mass and obesity-associated (FTO) gene in endometrial tumor tissues and further explored its role in β-estradiol (E2)-induced endometrial cancer cell proliferation and invasion. IHC staining showed that FTO overexpressed in endometrial carcinoma. Additionally, E2-induced FTO via activation of the PI3K/AKT and MPAK signal pathways contributed to enhanced proliferation and invasion. Therefore, this study provides a new insight on the mechanisms of E2-induced proliferation and invasion and the link between obesity and endometrial cancer, implying the possibility of using FTO as a potential therapeutic target for the treatment of endometrial cancer.
    Cancer letters 01/2012; 319(1):89-97. DOI:10.1016/j.canlet.2011.12.033 · 5.02 Impact Factor