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...

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