Association of a HOXB13 Variant with Breast Cancer

New England Journal of Medicine (Impact Factor: 55.87). 08/2012; 367(5):480-1. DOI: 10.1056/NEJMc1205138
Source: PubMed
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    • "Aberrant expression and methylation-dependent expression of the HOXB13 gene has been shown in cancer [13,14]. However, mutations within the HOXB13 gene and the linkage analyses of the neighboring 17q21–22 region found this region to be involved in the development of different cancers [15,16]. Our findings support those observations, and the fact that our results seem to indicate deactivation of only one allele by DNA methylation makes this phenomenon even more intriguing. "
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    ABSTRACT: Despite similar clinical and pathological features, large numbers of breast cancer patients experience different outcomes of the disease. This together with the fact that the incidence of breast cancer is growing worldwide emphasizes an urgent need for identification of new biomarkers for early cancer detection and stratification of patients. We used ultra high-resolution microarrays to compare genome-wide methylation patterns of breast carcinomas (N = 20) and non-malignant breast tissue (N = 5). Biomarker properties of a subset of discovered differentially methylated regions (DMRs) was validated using Methylation Sensitive High Resolution Melting (MS-HRM) in a case control study on a panel of breast carcinomas (N = 275) and non-malignant controls (N = 74). Based on microarray results we selected 19 DMRs for large-scale screening of cases and controls. Analysis of the screening results showed that all DMRs tested displayed significant gains of methylation in the cancer tissue when compared to the levels in control tissue. Interestingly, we have observed two types of locus specific methylation, with loci undergoing either predominantly full or heterogeneous methylation during carcinogenesis. At the same time almost all tested DMRs (17 out of 19) displayed low-level methylation in non-malignant breast tissue independent of locus specific methylation pattern in cases. Specific loci can undergo either heterogeneous or full methylation during carcinogenesis, and loci hypermethylated in cancer frequently show low-level methylation in non-malignant tissue.
    Breast cancer research: BCR 02/2014; 16(1):R17. DOI:10.1186/bcr3612 · 5.49 Impact Factor
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    ABSTRACT: Recently, the HOXB13 gene has been shown to be a susceptibility gene for prostate cancer. HOXB13 is overexpressed in breast cancer tissues and HOXB13 expression in combination with low expression of IL17BR is predictive for a tamoxifen response in ER-positive breast cancers. Based on observations, we hypothesized that the HOXB13 p.Gly84Glu mutation might be associated with breast cancer risk. We genotyped this mutation in the germline DNA of 4,037 women with breast cancer (including 1,082 familial cases) and in 2,762 controls from Canada and Poland. Seven heterozygous carriers of the HOXB13 p.Gly84Glu mutation were found in the cases (0.17 %) compared to four carriers among the controls (0.14 %; OR = 1.2, 95 % CI = 0.34-4.1, p = 1.0). Only one of the seven carriers had a family history of breast cancer. This study does not support the hypothesis that women who carry the HOXB13 Gly84Glu mutation are at increased risk of breast cancer.
    Breast Cancer Research and Treatment 10/2012; 136(3). DOI:10.1007/s10549-012-2295-y · 3.94 Impact Factor
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    ABSTRACT: BACKGROUND: Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans. METHODS: We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case-control study of more aggressive disease (N=2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans. RESULTS: In our studies the mutation was found exclusively among men with prostate cancer (carrier frequency=1.48%) or unaffected brothers of cases carrying the mutation (frequency=0.34%), and carrying the mutation gave an odds ratio for disease=4.79 (P=0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P=3.5x10-17), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P<1x10-5. CONCLUSIONS: The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men. Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer.
    Cancer Epidemiology Biomarkers & Prevention 02/2013; 22(4). DOI:10.1158/1055-9965.EPI-12-1154 · 4.13 Impact Factor
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