International Journal of Clinical Case Reports 2024, Vol.14, No.4, 202-209 http://medscipublisher.com/index.php/ijccr 203 2 Genetic Analysis of HOXB13Gene Variants 2.1 Overview of the structure and function of the HOXB13 gene The HOXB13 gene, located on chromosome 17q21, is a member of the Homeobox gene family, which encodes transcription factors responsible for regulating the development of various tissues. In particular, HOXB13 plays a key role in the differentiation and development of the prostate gland, influencing androgen receptor (AR) signaling (Tilki et al., 2016). The G84E mutation in HOXB13 has been identified as a significant genetic variant, conferring susceptibility to prostate cancer. The gene comprises two main exons that encode a protein critical for maintaining normal prostate function. Mutations in the HOXB13 gene disrupt these processes, contributing to cancer development by promoting uncontrolled cell proliferation (Sipeky et al., 2018). 2.2 Types of HOXB13 gene mutations and their distribution in prostate cancer The G84E variant (rs138213197) is the most studied mutation in the HOXB13 gene, predominantly associated with hereditary prostate cancer. This mutation is characterized by a guanine-to-adenine substitution, leading to the replacement of glycine with glutamic acid at position 84. It has been linked to increased prostate cancer risk, especially in men of European descent (Boyle et al., 2020). Other rare variants, such as G132E and F127C, have also been reported in specific populations, such as in Japanese men with familial prostate cancer (Kurihara et al., 2022). These mutations vary significantly across different geographic and ethnic groups, affecting risk levels and disease severity (Lotan et al., 2017). 2.3 Studies on the association betweenHOXB13 gene variants and the risk of prostate cancer Multiple studies have established a strong link between HOXB13 mutations and an increased risk of prostate cancer. The G84E variant, in particular, has been identified as a moderate-penetrance mutation that significantly increases the risk of developing prostate cancer, especially in men with a family history of the disease. Research by Dupont et al. (2021) found that carriers of the G84Emutation have up to an 8-fold increased risk of developing prostate cancer compared to non-carriers, especially those diagnosed with early-onset or aggressive forms of the disease. Additional studies have shown that the mutation is prevalent in approximately 1.5% of prostate cancer cases but is absent or rare in non-cancer populations (Kote-Jarai et al., 2015). Furthermore, studies conducted in diverse populations, including Finnish and British men, emphasize the mutation’s role in familial prostate cancer predisposition (Sipeky et al., 2018). 2.4 Influence of ethnicity, family history, and other genetic factors onHOXB13 variants The distribution and impact of HOXB13 variants, particularly the G84Emutation, show significant variation based on ethnicity and familial predisposition (Wang, 2024). Studies have found that G84E is predominantly prevalent among men of European descent, where it is strongly associated with familial prostate cancer. In contrast, other mutations such as G132E and F127C have been identified in Japanese populations, with varying degrees of risk implication (Kurihara et al., 2022). The risk of developing prostate cancer for HOXB13 mutation carriers also increases significantly in those with a positive family history of the disease. Additionally, HOXB13 mutations can interact synergistically with other genetic variants, such as CIP2A mutations, to further exacerbate disease risk, particularly in aggressive and early-onset cases (Sipeky et al., 2018). 3 Molecular Mechanisms of HOXB13Gene Variants 3.1 Impact of HOXB13 gene variants on gene expression and regulatory pathways The HOXB13 gene plays a key role in regulating gene expression through its function as a transcription factor. Variants in HOXB13, particularly the G84E mutation, have been shown to alter gene expression patterns in prostate cancer cells, influencing pathways involved in cell proliferation and metastasis (Heise et al., 2019). HOXB13 binds to androgen receptor (AR)-regulated elements and modulates the activity of genes involved in prostate development and tumor progression. Studies suggest that HOXB13 regulates mitotic protein-kinase interaction networks in metastatic prostate cancers, driving aggressive cancer phenotypes by activating a subset of genes essential for cancer cell proliferation and migration (Figure 1) (Yao et al., 2019).
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