Genetics of Prostate Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Genes With Potential Clinical Relevance in Prostate Cancer Risk
Table 6. Case-Control Studies ofBRCA1andBRCA2and Survival Outcomes continued...
Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer. Fine-mapping of this region provided strong evidence of linkage (LOD score = 5.49) and a narrow candidate interval (15.5 Mb) for a putative susceptibility gene among 147 families with four or more affected men and average age at diagnosis of 65 years or younger. The exons of 200 genes in the 17q21-22 region were sequenced in DNA from 94 unrelated patients from hereditary prostate cancer families (from the UM-PCGP and Johns Hopkins).Probands from four families were discovered to have a recurrent mutation (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the mutation. The mutation status was determined in 5,083 additional case subjects and 2,662 control subjects. Carrier frequencies and odds ratios for prostate cancer risk were as follows:
- Men with a positive family history of prostate cancer: 2.2% versus negative: 0.8% (OR, 2.8; 95% CI, 1.6–5.1; P = 1.2 × 10-4).
- Men with an age at diagnosis younger than 55 years: 2.2% versus older than 55 years: 0.8% (OR, 2.7; 95% CI, 1.6–4.7; P = 1.1 × 10-4).
- Men with a positive family history of prostate cancer and age at diagnosis younger than 55 years: 3.1% versus a negative family history of prostate cancer and age at diagnosis older than 55 years: 0.6% (OR, 5.1; 95% CI, 2.4–12.2; P = 2.0 × 10-6).
- Men with a positive family history of prostate cancer and age at diagnosis older than 55 years: 1.2%.
- Control subjects: 0.1% to 0.2%.
Additional rare variants in HOXB13 were also observed. Penetrance estimates of the G84E variant in HOXB13 are under study. HOXB13 plays a role in prostate development and binds to the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene proven to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer, but the clinical utility of testing for this mutation has not yet been defined.
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