Article

Association of a HOXB13 Variant with Breast Cancer

New England Journal of Medicine (Impact Factor: 54.42). 08/2012; 367(5):480-1. DOI: 10.1056/NEJMc1205138
Source: PubMed
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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.
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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.
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    ABSTRACT: Introduction: The HOXB13 pGly84Glu mutation has recently been associated with an increased risk of prostate cancer but the association of other cancer sites with this allele has not been assessed. Data has suggested that HOXB13 expression levels are decreased in colorectal cancer (CRC) cell lines indicating this gene may be involved in colorectal tumourigenesis. Methods: To evaluate a potential association of this mutation with CRC, we genotyped the mutation in 2695 CRC cases and 4593 controls from population-based registries in Canada and Australia. Results: The HOXB13 pGly84Glu mutation was more common in CRC cases than controls (0.48% vs. 0.17%, P=0.02) indicating a significant association between the HOXB13 variant and CRC risk (OR=2.8; 95%CI: 1.2-6.8). This association was attenuated but remained significant with the inclusion of previously published and publicly available genotype data. Pedigree analysis of cases and controls revealed that 7/21 HOXB13 mutation carriers had a family history of prostate cancer. Discussion: This report is the first to suggest a risk of CRC associated with mutations in the HOXB13 gene. These findings require further validation but may be of importance in the screening and genetic counseling of families known to carry the HOXB13 pGly84Glu mutation.
    03/2013; 37(4). DOI:10.1016/j.canep.2013.03.003