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Area of Science:

  • Genetics
  • Oncology
  • Urology

Background:

  • The HOXB13 c.G251G>A:p.G84E variant (rs138213197) is linked to prostate cancer (PrCa) risk, but its association with aggressive PrCa is debated.
  • Limited large-scale population data exist for genetic counseling regarding this variant.

Purpose of the Study:

  • To evaluate the association between the HOXB13 p.G84E variant and prostate cancer risk in a large cohort.
  • To determine if the HOXB13 p.G84E variant influences PrCa aggressiveness.

Main Methods:

  • Analysis of 592,158 male participants from the Veterans Health Administration (VA) Million Veteran Program (MVP).
  • Identification of individuals heterozygous for HOXB13 p.G84E.
  • Use of Cox proportional hazards models and multivariable logistic regression to assess PrCa risk and diagnosis.

Main Results:

  • HOXB13 p.G84E heterozygosity significantly increased the risk of any PrCa (HR, 3.17), metastatic PrCa (HR, 2.99), and PrCa-specific mortality (HR, 2.63).
  • In a subset, heterozygotes had a higher risk of PrCa diagnosis (OR, 2.60).
  • PrCa in heterozygotes occurred at younger ages but showed similar aggressiveness (Gleason scores) and metastatic rates.

Conclusions:

  • The HOXB13 p.G84E variant is associated with a moderately increased lifetime risk of PrCa.
  • PrCa associated with this variant is not more aggressive but may be diagnosed earlier.
  • Further research is needed to assess the benefit of early PrCa screening in HOXB13 p.G84E heterozygotes.