HOXB13 – Prostate Cancer

HOXB13 is a homeobox transcription factor critical for prostate development and implicated in hereditary prostate cancer risk. A recurrent germline missense variant, c.251G>A (p.Gly84Glu), has been identified in multiple high‐risk families and unrelated case‐control cohorts, establishing HOXB13 as a prostate cancer susceptibility gene. The association follows autosomal dominant inheritance with high penetrance and variable expressivity. Early‐onset, familial, and aggressive prostate cancer cases are enriched for the G84E allele, which co‐segregates with disease in pedigrees and shows a founder effect in populations of European descent.

Clinical Validity

Extensive evidence from linkage and sequencing studies supports a definitive gene–disease association. In four large families, all 18 affected men carried the G84E variant (segregation n = 18) ([PMID:22236224]). In a case‐control series of 5 083 European‐descent cases and 1 401 controls, the variant was found in 72 cases versus 1 control (OR ≈ 20) ([PMID:22236224]). Independent replication in familial cohorts (928 probands, 16 carriers; OR = 7.9) and population‐based series confirms the finding with strong segregation and functional concordance.

Genetic Evidence

Inheritance mode: Autosomal dominant. Segregation: 18 additional affected relatives in four pedigrees ([PMID:22236224]). Case‐control: 72/5083 cases versus 1/1401 controls; 16/928 familial probands versus 2/930 controls ([PMID:22236224]; [PMID:22714734]). Variant spectrum: predominantly missense (p.Gly84Glu), with rare alternate alleles including c.646G>T (p.Gly216Cys) and c.685C>G (p.Arg229Gly). Founder effect supported by haplotype analyses in Finnish and Swedish populations ([PMID:22841674]).

Functional Evidence

Mechanism: Gain‐of‐function through altered coactivation of androgen receptor and FOXA1, and dysregulated gene expression. In vitro assays show G84E modulates enhancer activity, increases prostate cancer cell proliferation, and alters receptor binding dynamics ([PMID:25206306]). HOXB13–MEIS1 interaction studies demonstrate that MEIS1 stabilizes HOXB13 protein and that knockdown of both genes synergistically reduces proliferation, confirming functional relevance in prostate carcinogenesis ([PMID:30560549]).

Integration and Clinical Utility

The definitive association of HOXB13 G84E with autosomal dominant prostate cancer, supported by robust segregation, case‐control enrichment, and mechanistic data, underpins its use in genetic testing and risk stratification. Identification of carriers informs tailored surveillance, early detection strategies, and potential therapeutic targeting of androgen signaling pathways. HOXB13 genotyping has clear implications for familial screening and clinical decision‐making.

Key Take-home: Germline HOXB13 c.251G>A (p.Gly84Glu) testing enables identification of high‐risk individuals for autosomal dominant prostate cancer, guiding surveillance and management.

References

• N Engl J Med • 2012 • Germline mutations in HOXB13 and prostate-cancer risk PMID:22236224
• J Natl Cancer Inst • 2012 • Association between germline HOXB13 G84E mutation and risk of prostate cancer PMID:22781434
• J Natl Cancer Inst • 2020 • Germline pathogenic variants in 7636 Japanese patients with prostate cancer and 12 366 controls PMID:31214711
• Pharmacogenomics and personalized medicine • 2014 • Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer PMID:25206306
• The Prostate • 2019 • HOXB13 interaction with MEIS1 modifies proliferation and gene expression in prostate cancer PMID:30560549

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