Prostate cancer risk variants of the HOXB genetic locus

Sci Rep. 2021 May 31;11(1):11385. doi: 10.1038/s41598-021-89399-7.


The G84E germline mutation of HOXB13 predisposes to prostate cancer and is clinically tested for familial cancer care. We investigated the HOXB locus to define a potentially broader contribution to prostate cancer heritability. We sought HOXB locus germline variants altering prostate cancer risk in three European-ancestry case-control study populations (combined 7812 cases and 5047 controls): the International Consortium for Prostate Cancer Genetics Study; the Nashville Familial Prostate Cancer Study; and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Multiple rare genetic variants had concordant and strong risk effects in these study populations and exceeded genome-wide significance. Independent risk signals were best detected by sentinel variants rs559612720 within SKAP1 (OR = 8.1, P = 2E-9) and rs138213197 (G84E) within HOXB13 (OR = 5.6, P = 2E-11), separated by 567 kb. Half of carriers inherited both risk alleles, while others inherited either alone. Under mutual adjustment, the variants separately carried 3.6- and 3.1-fold risk, respectively, while joint inheritance carried 11.3-fold risk. These risks were further accentuated among men meeting criteria for hereditary prostate cancer, and further still for those with early-onset or aggressive disease. Among hereditary prostate cancer cases diagnosed under age 60 and with aggressive disease, joint inheritance carried a risk of OR = 27.7 relative to controls, P = 2E-8. The HOXB sentinel variant pair more fully captured genetic risk for prostate cancer within the study populations than either variant alone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Case-Control Studies
  • Genetic Predisposition to Disease*
  • Genotype
  • Homeodomain Proteins / genetics*
  • Humans
  • Male
  • Middle Aged
  • Prostatic Neoplasms / genetics*


  • HOXB13 protein, human
  • Homeodomain Proteins