What is the HOXB13 (Homeobox B13) mutation?

HOXB13 Mutation and Prostate Cancer Risk

The HOXB13 G84E mutation is a rare but significant genetic variant strongly associated with hereditary prostate cancer risk, increasing the likelihood of developing prostate cancer by approximately 3.5-fold compared to non-carriers. 1

What is HOXB13?

• HOXB13 is a homeobox transcription factor gene that plays a critical role in prostate gland development and differentiation 2
• Located on chromosome 17q21-22, a region previously implicated in prostate cancer susceptibility through linkage studies 3
• The G84E mutation (rs138213197) is the most well-studied variant of HOXB13 associated with prostate cancer risk 3, 4

Clinical Significance of HOXB13 G84E Mutation

Prostate Cancer Risk

• Carriers have approximately 3.4-3.5 times higher risk of developing prostate cancer compared to non-carriers 4
• The absolute lifetime risk (by age 80) for G84E carriers is estimated at 33%, compared to 12% for non-carriers 4
• Risk is particularly elevated for:
  • Early-onset prostate cancer (OR: 8.6) 4
  • Hereditary prostate cancer (OR: 6.6) 4
  • Men with positive family history of prostate cancer 5, 6

Prevalence

• The mutation is found in approximately 1.3-1.4% of men with prostate cancer of European descent 3, 4
• Higher prevalence (3.1%) in men with early-onset, familial prostate cancer 3
• Much rarer (0.1-0.2%) in control populations without prostate cancer 3, 4
• Considered a founder mutation primarily in populations of Northern European ancestry 4

Clinical Implications and Management

Genetic Testing Recommendations

• Strong consensus (95%) exists to test for HOXB13 mutations in suspected hereditary prostate cancer 1
• Testing should be considered for individuals with:
  • Three or more first-degree relatives with prostate cancer 1
  • Two or more cases of prostate cancer diagnosed before age 55 1
  • Aggressive prostate cancer (Gleason score ≥7) and two or more cases of breast, ovarian, or pancreatic cancer in the family 1

Prostate Cancer Screening

• HOXB13 mutation status should be factored into prostate cancer screening discussions (53% consensus) 1
• Screening recommendations may include:
  • Earlier baseline PSA testing
  • More frequent screening intervals 1
  • Consideration of family history in determining screening protocols 5

Risk Modification

• Risk for HOXB13 G84E carriers varies based on:
  • Family history of prostate cancer 5
  • Birth cohort (higher relative risks observed in men born after 1930) 5
  • Presence of other genetic risk factors 4

Important Considerations

• Risk assessment should be personalized based on the individual's complete family history 5
• The combination of HOXB13 G84E mutation with other genetic risk factors (polygenic risk score) can further increase lifetime risk to 48% 4
• HOXB13 expression is retained in the majority of prostate cancers, including advanced and metastatic disease, making it a useful diagnostic biomarker 2
• Genetic counseling should be provided before and after testing to ensure proper understanding of risk implications 1