HOXB13 G84E-related Familial Prostate Cancers A Clinical, Histologic, and Molecular Survey

Recent genetic epidemiologic studies identified a germline mutation in the homeobox transcription factor, HOXB13 G84E, which is associated with markedly increased risk for prostate cancer, particularly early-onset hereditary prostate cancer. The histomorphologic and molecular features of cancers arising in such carriers have not been studied. Here, we reviewed prostatectomy specimens from 23 HOXB13 G84E mutation carriers, mapping the total cancer burden by anatomically distinct cancer focus and evaluating morphologic features. We also assessed basic molecular subtypes for all cancer foci (ERG/SPINK1 status) by dual immunohistochemistry staining on full sections. The cohort showed a median age of 58 years, a median serum PSA level of 5.7 ng/mL, and a median of 6 cancer foci (range, 1 to 14) per case. Of evaluable cases, dominant foci were Gleason score 6 in 23%, 3+4=7 in 41%, 4+3=7 in 23%, and >= 8 in 14%; biochemical recurrence was observed in 1 case over a median of 36 months follow-up. Histologic review found a high prevalence of cases showing cancers with a spectrum of features previously described with pseudohyperplastic carcinomas, with 45% of cases showing a dominant focus with such features. Molecular subtyping revealed a strikingly low prevalence of ERG(+) cancer with increased prevalence of SPINK1(+) cancer (dominant focus ERG(+) 17%, SPINK1(+) 26%, ERG(-)/SPINK1(-) 52%, single ERG(+)/SPINK1(+) focus 4%). One ERG(-)/SPINK1(-) dominant focus showed aberrant p63(+) immunophenotype. In summary, HOXB13 G84E variant-related prostate cancers show frequent pseudohyperplastic-type features and markedly low prevalence of ERG(+) cancers relative to unselected cases and, especially, to early-onset cohorts. These findings suggest that novel molecular pathways may drive disease in HOXB13 G84E carriers.