Dissecting the Role of a Germline HOXB13 Variant Associated with Risk of Lethal Prostate Cancer in Men of African Ancestry
Abstract
The proposed studies will focus on a gene named HOXB13, and an altered protein, named X285K, made by an altered or mutated form of this gene, in some men of African descent when inherited from their parents. We assembled an expert team including investigators with a long history of studying prostate cancer in African American men to investigate the functional and treatment implications of this novel risk variant. Historically, genetic variants associated with prostate cancer were notoriously challenging to validate. HOXB13 was the first bona fide prostate cancer gene implicated in risk for the disease following the discovery of the European ancestry specific G84E variant (published in the New England Journal of Medicine in 2012 by one of our co-investigators). However, the association between G84E and prostate cancer risk was equally strong in men with aggressive and non-aggressive disease. Recently, we and others investigated a novel stop-loss HOXB13 variant (X285K). One unique property of the X285K variant that sets it apart from all other HOXB13 variants is its association with risk of aggressive and potentially lethal prostate cancer specifically in men of African ancestry. In our humble opinion, X285K is quite possibly the most important marker identified to date for lethal prostate cancer risk in the African American population. Nevertheless, genetic association of X285K with aggressive prostate cancer is the only information currently available, limiting its clinical utility. Our goal is to dissect the functional and treatment implications of this unique germline variant. We hypothesize that X285K mediates an aggressive phenotype associated with cell-cycle dysregulation, and this unique property manifests clinically as early diagnosis of potentially lethal prostate cancer and also hormonal insensitivity. We propose a series of detailed functional and mechanistic analyses focusing on the comparison of X285K, G84E, and their normal or wild type counterpart. The proposed studies will use unique tools and resources developed during the initial studies, and will be necessary in order to strategize the proper use of genetic testing results to benefit patients and their families. This unique variant therefore presents opportunities to make tangible impact on patients and their families in the short term. Treatment implications of the X285K variant, if established in the study, will enable actionable interventions in men with self-identified African ancestry and will help to mitigate the disproportionate burden of prostate cancer by informing genetic testing strategies. We envision that adoption of genetic testing and early screening in high-risk populations can be facilitated by public dissemination of our findings on a rare variant, and early screening is one of the strategies that will result in early detection and early treatment of life-threatening prostate cancer. In addition, for men who are diagnosed with advanced prostate cancer, genetic testing is available but X285K is currently not reported in testing results. If our proposal studies confirm the treatment implications, the test result may inform treatment decisions, and optimal treatment selection will improve patient outcome and quality of life. The proposed studies will also help to understand the roles of germline HOXB13 variants in prostate cancer. In the long term, knowledge on these heritable risk variants will benefit all men and their families especially given the recent interest in using HOXB13 as a therapeutic target. In the United States, prostate cancer is a prevalent disease that is also well known to disproportionately affect African American men. Development of actionable interventions targeting ancestry-specific or ancestry- enriched mutations, germline or somatic, remains an important approach to mitigate prostate cancer disparity. This application will address three FY22 PCRP Overarching Challenges: (1) Develop trea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310612
Entities
People
- Jun Luo
Organizations
- Johns Hopkins University
- United States Army