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      Germline HOXB13 p.Gly84Glu mutation and cancer susceptibility: a pooled analysis of 25 epidemiological studies with 145,257 participates

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          Abstract

          Numerous studies have investigated association between the germline HOXB13 p.Gly84Glu mutation and cancer risk. However, the results were inconsistent. Herein, we performed this meta-analysis to get a precise conclusion of the associations. A comprehensive literature search was conducted through Medline (mainly Pubmed), Embase, Cochrane Library databases. Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated by STATA 12.1 software to evaluate the association of HOXB13 p.Gly84Glu mutation and cancer susceptibility. Then, 25 studies including 51,390 cases and 93,867 controls were included, and there was significant association between HOXB13 p.Gly84Glu mutation and overall cancer risk (OR = 2.872, 95% CI = 2.121–3.888, P < 0.001), particularly in prostate cancer (OR = 3.248, 95% CI = 2.313–4.560, P < 0.001), while no association was found in breast (OR = 1.424, 95% CI = 0.776–2.613, P = 0.253) and colorectal cancers (OR = 2.070, 95% CI = 0.485–8.841, P = 0.326). When we stratified analysis by ethnicity, significant association was found in Caucasians (OR = 2.673, 95%CI = 1.920–3.720, P < 0.001). Further well-designed with large samples and other various cancers should be performed to validate our results.

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          Germline mutations in HOXB13 and prostate-cancer risk.

          Charles Ewing, Anna Ray, Ethan Lange … (2012)
          Family history is a significant risk factor for prostate cancer, although the molecular basis for this association is poorly understood. Linkage studies have implicated chromosome 17q21-22 as a possible location of a prostate-cancer susceptibility gene. We screened more than 200 genes in the 17q21-22 region by sequencing germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. We tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. Probands from four families were discovered to have a rare but recurrent mutation (G84E) in HOXB13 (rs138213197), a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these four families carried the mutation. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1401 control subjects (0.1%) (P=8.5x10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P=2.0x10(-6)). The novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer. (Funded by the National Institutes of Health and others.).
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            The homeodomain protein HOXB13 regulates the cellular response to androgens.

            Mark McDonnell, H. Cui, Bryan M. Wittmann … (2009)
            HOXB13 is a member of the homeodomain family of sequence-specific transcription factors and, together with the androgen receptor (AR), plays a critical role in the normal development of the prostate gland. We demonstrate here that, in prostate cancer cells, HOXB13 is a key determinant of the response to androgens. Specifically, it was determined that HOXB13 interacts with the DNA-binding domain of AR and inhibits the transcription of genes that contain an androgen-response element (ARE). In contrast, the AR:HOXB13 complex confers androgen responsiveness to promoters that contain a specific HOXB13-response element. Further, HOXB13 and AR synergize to enhance the transcription of genes that contain a HOX element juxtaposed to an ARE. The profound effects of HOXB13 knockdown on androgen-regulated proliferation, migration, and lipogenesis in prostate cancer cells highlight the importance of the observed changes in gene expression.
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              A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer.

              Julius Gudmundsson, Patrick Sulem, Daniel Gudbjartsson … (2012)
              In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 8 December 2015
                Publication date (Electronic): 17 October 2015
                Volume: 6
                Issue: 39
                Pages: 42312-42321
                Affiliations
                1 Department of Urology, Tianjin Institute of Urology, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China
                2 Department of Radiotherapy, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China
                3 Pharmaceutical Department, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China
                4 Library of Tianjin Medical University, Tianjin Medical University, Tianjin, 300070, China
                5 Tianjin Institute of infectious diseases, the Second Hospital of Tianjin Medical University, Tianjin, 300211, China
                Author notes
                Correspondence to: Yan Zhao, zhaoyan2010109@ 123456163.com
                Article
                DOI: 10.18632/oncotarget.5994
                PMC ID: 4747227
                PubMed ID: 26517352
                SO-VID: 5cc8c693-be8e-410b-a056-ef7af84a34a3
                Copyright © Copyright: © 2015 Cai et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 1 August 2015
                Date accepted : 5 October 2015
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: hoxb13 gene,rs138213197,genetic mutation,cancer,risk
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: hoxb13 gene, rs138213197, genetic mutation, cancer, risk

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