• Major finding:HOXB13 G84E mutation is associated with hereditary prostate cancer risk.

  • Approach: Linkage analysis and targeted sequencing identified G84E in prostate cancer families.

  • Impact: Men with early-onset hereditary prostate cancer more frequently carry HOXB13 G84E.

A positive family history is a known risk factor for the development of prostate cancer, but specific germline mutations have not yet been identified. Linkage analyses of families with hereditary disease have pointed to chromosome 17q21-22 as a possible genetic susceptibility locus. Using fine-mapping studies combined with targeted sequencing of 202 genes in this region, Ewing and colleagues found that a mutation in the HOXB13 gene, resulting in a nonconservative glycine-to-glutamic acid substitution (G84E), is significantly associated with increased risk of hereditary prostate cancer. HOXB13, which encodes a transcription factor belonging to the highly conserved homeobox gene family, plays a role in normal prostate development. The G84E variant was identified first in probands from 4 families with hereditary prostate cancer and consequently confirmed in all affected members of these families. Additional genetic analyses revealed a HOXB13 G84E carrier frequency of 1.4% in men with familial prostate cancer compared with 0.1% in nonaffected controls. Importantly, the highest carrier frequency (3.1%) was found in men with both a positive family history and an early diagnosis of prostate cancer. G84E and 4 other rare HOXB13 mutations identified in 2 families and 2 prostate cancer cell lines are located in highly conserved functional protein domains. Although the mechanistic role of HOXB13 G84E in carcinogenesis remains unknown, the findings presented here offer insight into the genetic basis of prostate cancer and may have clinical implications for families with hereditary disease.

Ewing CM, Ray AM, Lange EM, Zuhlke KA, Robbins CM, Tembe WD, et al. Germline mutations in HOXB13 and prostate cancer risk. N Engl J Med 2012;366:141–9.

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