Clinical and Functional Analyses of an African-Ancestry Gain-of-function HOXB13 Variant Implicated in Aggressive Prostate Cancer - Beyond the Abstract
First, in prostate cancer patients ordering this test through the Detect Hereditary Prostate Cancer (DHPC) program run by the Invitae Corporation from 2019-2022, we found X285K was significantly enriched in self-reported Black (1.01%) versus White (0.01%) patients, and X285K carriers had aggressive disease features similar to BRCA2 pathogenic/likely pathogenic (P/LP) carriers, but more aggressive than carriers of the HOXB13 (G84E) variant which was enriched in self-reported White versus Black patients (1.12% vs 0.11%). Second, we discovered a unique gain-of-function oncogenic mechanism of X285K, as the replacement of the wild-type HOXB13 with the mutant elevated an expression signature associated with cell cycle progression and the E2F/MYC signature, while its function of regulating AR-target genes largely remains intact. Third, this gain-of-function, which is very different from the loss-of-functions seen in other pathogenic variants, can be explained by the enhanced (i.e., gained) ability of X285K in epigenetic regulation of the target genes cyclin B1 and c-Myc. We conclude that the HOXB13 (X285K) variant is clinically and functionally linked to aggressive prostate cancer, supporting genetic testing for X285K in Black men and early disease screening of carriers of this variant. We are hoping that this study facilitates early detection of prostate cancer in X285K carriers within the window of cure. We are also actively researching therapies that may target this specific mutation.
Written by: Mayuko Kanayama, MD, PhD, Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD
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