Prostate Cancer, Hereditary, 9

A number sign (#) is used with this entry because of evidence that susceptibility to hereditary prostate cancer-9 (HPC9) is associated with variation in the HOXB13 gene (604607) on chromosome 17q21-q22.

Lange et al. (2003) performed linkage analysis on 175 pedigrees with prostate cancer, most of whom contained 3 or more affected individuals. A candidate locus was identified on chromosome 17q (nonparametric lod score of 2.36), with strongest evidence coming from a subset of pedigrees with 4 or more affected individuals (nonparametric lod score of 3.27).

By linkage analysis of 453 pedigrees with prostate cancer, including the 175 pedigrees analyzed by Lange et al. (2003), Lange et al. (2007) found linkage to 17q21-q22 (maximum lod score of 2.99 near marker D17S1820). A subset of 147 families with 4 or more cases of prostate cancer and an average age at diagnosis of less than or equal to 65 years resulted in a maximum lod score of 5.49 near the same marker.

To identify a prostate cancer susceptibility gene in the 17q21-q22 region, Ewing et al. (2012) sequenced 2,009 exons from 202 genes in germline DNA from 94 unrelated patients with prostate cancer from families selected for linkage to the candidate region. They then tested family members, additional case subjects, and control subjects to characterize the frequency of the identified mutations. Probands from 4 families were discovered to have a rare but recurrent mutation, G84E (rs138213197; 604607.0001), in HOXB13, a homeobox transcription factor gene that is important in prostate development. All 18 men with prostate cancer and available DNA in these 4 families carried the mutation. At the time of the analysis the G84E mutation was not reported in dbSNP or in the NCBI 1000 Genomes sequencing project, which included 1,094 subjects, 381 of European descent. The carrier rate of the G84E mutation was increased by a factor of approximately 20 in 5,083 unrelated subjects of European descent who had prostate cancer, with the mutation found in 72 subjects (1.4%), as compared with 1 in 1,401 control subjects (0.1%) (P = 8.5 x 10(-7)). The mutation was significantly more common in men with early-onset, familial prostate cancer (3.1%) than in those with late-onset, nonfamilial prostate cancer (0.6%) (P = 2.0 x 10(-6)). Ewing et al. (2012) concluded that this novel HOXB13 G84E variant is associated with a significantly increased risk of hereditary prostate cancer. Ewing et al. (2012) identified 4 additional rare HOXB13 mutations, 1 in the same MEIS interaction domain where the G84E mutation is located, 1 in a second MEIS binding domain, and 2 in the homeodomain.

Huang et al. (2014) found that a prostate cancer risk-associated SNP on chromosome 6q22, rs339331, lies within an evolutionarily conserved region in intron 4 of the transcription factor RFX6 gene (612659) that functions as a HOXB13-binding site. The risk-associated T allele at rs339331 increases binding of HOXB13 to a transcriptional enhancer, conferring allele-specific upregulation of RFX6. Suppression of RFX6 diminishes prostate cancer cell proliferation, migration, and invasion. Clinical data indicated that RFX6 upregulation in human prostate cancers correlates with tumor progression, metastasis, and risk of biochemical relapse. Huang et al. (2014) observed a significant association between the risk-associated T allele at rs339331 and increased RFX6 mRNA levels in human prostate tumors. The authors concluded that rs339331 affects prostate cancer risk by altering RFX6 expression through a functional interaction with the prostate cancer susceptibility gene HOXB13.