HOXB13 G84E–related Familial Prostate Cancers

Abstract

Recent genetic epidemiologic studies identified a germline mutation in the homeobox transcription factor, HOXB13 G84E, which is associated with markedly increased risk of 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 median age 58 years, median serum PSA 5.7 ng/ml, and a median of 6 cancer foci (range 1–14) 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 one 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.

Prostate Cancer SubtyPINg BiomarKers and Outcome: Is Clarity EmERGing?

“…Interestingly, in the three ERG + /SPINK1 + cases evaluated on whole sections by Flavin et al . and in the one observed in our recent series(12), only small areas of dual positivity were observed in otherwise ERG + /SPINK1 − foci. Such observations underscore the value of whole section-based studies, and, given the lack of a homogeneous ERG + /SPINK1 + tumor foci, these exceptions seem to prove the rule observed at the transcript level.…”

“…If ERG rearrangements occurred at any point in PCa development and progression, one would expect to observe with some frequency small pockets of nascent ERG + cancer arising within large ERG − tumor foci, which has never been reported. In contrast, we and others have published examples of apparent ERG + /ERG − , ERG + /ETV1 + and ERG + /SPOP mut cases which represent “collisions” of genetically distinct foci on whole section evaluation(4, 8, 11, 12). …”

“…Such observations underscore the value of whole section-based studies, and, given the lack of a homogeneous ERG + /SPINK1 + tumor foci, these exceptions seem to prove the rule observed at the transcript level. Lastly, and importantly with respect to criteria for positivity, in whole section based studies, we commonly observe heterogeneous SPINK1 expression, both in intensity and percentage, with particularly strong staining in the leading edge of tumors (8, 12). Given the lack of prognostic ability of SPINK1 in prostatectomy series, the major near term utility of this biomarker will likely be in subtyping.…”

Prostat Kanser Patolojisi

“…Psödohiperplastik görünüm patolojik evreyi etkilemez [36]. HOXB13 G84E ile ilişkili ailevi prostat kanseri çok kez psödohi-perplastik özelliklere sahiptir [37].…”

Computational Modeling of complete HOXB13 protein for predicting the functional effect of SNPs and the associated role in hereditary prostate cancer

“…The human HOXB13 gene consists of two exons and three introns and encodes a 284 amino acid protein (NCBI: NP_006352.2) belonging to the homeobox gene family16. It encodes a transcription factor which plays a major role in normal prostate development1718.…”