HOXB13 is a susceptibility gene for prostate cancer: Results from the International Consortium for Prostate Cancer Genetics (ICPCG)

Data Coordinating Center for the ICPCG, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Human Genetics (Impact Factor: 4.82). 01/2013; 132(1):5-14. DOI: 10.1007/s00439-012-1229-4
Source: PubMed


Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10−8 [odds ratio 4.42 (95 % confidence interval 2.56–7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10−6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.

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Available from: Graham G Giles, Oct 03, 2015
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    • "Fusion of TMPRSS2 and ETS transcription factors genes occurs in approximately 50% of prostate cancer patients [11]. Moreover, BRCA1/2 [12], MMR genes [13], and HOXB13 [14] show potential clinical relevance in prostate cancer risk. Some studies showed LOH and chromosomal aberrations in prostate tumors [15–17]. "
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    ABSTRACT: Prostate cancer is the most common noncutaneous cancer among men in the United States. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular mechanisms involved in prostate cancer initiation is still not well understood. Loss of heterozygosity (LOH) of chromosomal regions is crucial in tumor progression. In human prostate cancer, several chromosomal regions demonstrating a high frequency of LOH have been previously identified. KCTD11 (REN) is a tumor suppressor gene mapping on human chromosome 17p13.2, whose expression is frequently lost in human medulloblastoma and in several other cancer types. KCTD11 acts as a negative regulator of the Hedgehog (Hh) signaling. Here, we demonstrated that KCTD11 LOH is a common genetic lesion in human prostate adenocarcinoma. Indeed, nuclear KCTD11 protein expression is strongly reduced in primary prostate cancer, and this event correlated with overexpression of proteins acting into the Hedgehog pathway. Low levels of KCTD11 mRNA have been also observed in prostatic cancer cells, and ectopic overexpression of KCTD11 led to growth arrest. Our study demonstrates and supports that KCTD11, as well as negatively regulated downstream effectors belonging to Hh signaling, plays a role in prostate cancer pathogenesis. This could be suitable to characterize new diagnostic and therapeutic markers.
    BioMed Research International 06/2014; 2014:380398. DOI:10.1155/2014/380398 · 2.71 Impact Factor
  • Human Genetics 09/2012; 132(1). DOI:10.1007/s00439-012-1226-7 · 4.82 Impact Factor
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    ABSTRACT: BACKGROUND: A recently identified germline mutation G84E in HOXB13 was shown to increase the risk of prostate cancer (PrCa). In a family-based analysis by The International Consortium for Prostate Cancer Genetics, the proportion of G84E mutation was highest in families from the Nordic countries of Finland (22.4%) and Sweden (8.2%). METHODS: To further investigate the importance of G84E in the Finns, we determined its frequency in over 4000 PrCa cases and 5000 controls. In addition, the frequency was characterized in 986 breast (BrCa) and 442 colon cancer (CRC) cases. Genotyping was performed using TaqMan®, MassARRAY iPLEX and sequencing. Statistical analyses were performed using Fisher's exact test and overall survival was analyzed using Cox modeling. RESULTS: Frequency was significantly higher among patients with PrCa, and highest among patients with family history of the disease, i.e. hereditary PrCa (8.4% vs. 1.0% in controls; odds ratio 8.8; 95% CI 4.9-15.7). The mutation contributed significantly to younger age (≤55 years) at onset and high PSA (≥20 ng/ml) at diagnosis. An association with increased PrCa risk in patients with prior BPH diagnosis was also revealed. No statistically significant evidence for G84E contribution in CRC risk was detected but a suggestive role for the mutation was seen in familial BrCa negative for BRCA1/2 founder mutations. CONCLUSIONS: These findings confirm the increased risk effect of G84E mutation in the Finnish population, particularly for early-onset PrCa and cases with substantially elevated PSA. Impact: This study confirms the overall importance of the HOXB13 G84E mutation in prostate cancer susceptibility.
    Cancer Epidemiology Biomarkers & Prevention 01/2013; 22(3). DOI:10.1158/1055-9965.EPI-12-1000-T · 4.13 Impact Factor
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