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

Smith, Steven C. MD, PhD*; Palanisamy, Nallasivam PhD*,†,‡; Zuhlke, Kimberly A. BA§; Johnson, Anna M. MS§; Siddiqui, Javed MS*,†; Chinnaiyan, Arul M. MD, PhD*,†,‡,∥,¶; Kunju, Lakshmi P. MD*,†,‡; Cooney, Kathleen A. MD‡,§; Tomlins, Scott A. MD, PhD*,†,‡,¶

The American Journal of Surgical Pathology: May 2014 - Volume 38 - Issue 5 - p 615–626
doi: 10.1097/PAS.0000000000000090
Original Articles
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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.

Departments of *Pathology

§Internal Medicine

Urology

Michigan Center for Translational Pathology

Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI

Howard Hughes Medical Institute, Chevy Chase, MD

S.C.S. and N.P. contributed equally. S.C.S. current address: Department of Pathology, VCU Health System, Richmond, VA 23298.

Preliminary findings for this work was presented at the Annual Meeting of the United States and Canadian Academy of Pathology Meeting, Baltimore, MD, in March 2013.

Conflicts of Interest and Source of Funding: Supported in part by the Prostate Cancer Foundation, the University of Michigan Comprehensive Cancer Center Prostate SPORE (P50CA 069568), the National Institutes of Health (R01 CA 132874 to A.M.C. and R01 CA 79596 to K.A.C.), and the Early Detection Research Network (U01 CA111275 and U01 CA113913). A.M.C. and S.A.T. are supported by a Stand Up To Cancer — Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (SU2C-AACR-DT0712). A.M.C. is supported by the Prostate Cancer Foundation, Alfred A. Taubman Institute, the Howard Hughes Medical Institute, and a Doris Duke Charitable Foundation Clinical Scientist Award. N.P. and S.A.T. are supported by University of Michigan Prostate SPORE Career Development Awards. The University of Michigan has applied for a patent related to the identification of HOXB13 mutations in men with prostate cancer, on which K.A.C is listed as an inventor. The University of Michigan has been issued a patent on the detection of ETS gene fusions in prostate cancer, on which S.A.T. and A.M.C. are listed as co-inventors. The University of Michigan licensed the diagnostic field of use to Gen-Probe Inc., who has sublicensed some rights to Ventana Medical Systems-Roche. S.A.T. serves as a consultant to, and has received honoraria from, Ventana Medical Systems-Roche. A.M.C. has served as a consultant for Gen-Probe Inc. and Ventana Medical Systems-Roche. N.P. receives research funding from Ventana Medical Systems-Roche. Gen-Probe and Ventana Medical Systems-Roche did not play a role in the design and conduct of this study, in the collection, analysis, or interpretation of the data, or in the preparation, review, or approval of the article.

Correspondence: Scott A. Tomlins, MD, PhD, Department of Pathology, University of Michigan Medical School, 1524 Basic Sciences Research Building, 109 Zina Pitcher Place SPC 2200, Ann Arbor, MI 48109-2200 (e-mail: tomlinss@umich.edu).

© 2014 by Lippincott Williams & Wilkins.