Genetic Disorder Reference Sheet: HOXB13
An altered HOXB13 gene may increase a patient’s risk for developing prostate cancer. The HOXB13 gene is expressed in the prostate beginning in early development and affects prostate cell (https://doi.org/10.1200/PO.19.00284) proliferation and differentiation and androgen receptor regulation. When it acts as a tumor suppressor gene, HOXB13 codes for a protein that regulates cell division. However, altered copies of HOXB13 are inactivated, meaning that it does not function properly or does not produce the protein it codes for, resulting in uncontrolled cell division.
Although many cases of prostate cancer are detected early and remain localized, a subset involves more aggressive disease, leading to metastasis and significant morbidity and mortality. Researchers are working to identify individual factors that increase risk (https://doi.org/10.1200/PO.19.00284) in patients who might benefit from earlier and more intensive surveillance.
An estimated 5%–15% of prostate cancers are attributed to germline pathogenic variants (https://doi.org/10.1007/s40291-021-00529-3). Germline HOXB13 pathogenic variants have been consistently associated with prostate cancer risk and more aggressive prostate cancer, but their association with other cancer risks (https://doi.org/10.1038/s41416-020-01036-8) is unclear.
Germline Biomarker Testing
ONS recommends using germline biomarker testing as the preferred term to describe testing for inherited genetic changes, which helps clinicians identify individuals for earlier screening than recommended in the general public. Early diagnosis promotes potentially curable disease (https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html) and reduces risk of overtreatment, therapy-related side effects, and the need for systemic treatments, thereby decreasing overall healthcare costs.
Individuals with prostate cancer may be indicated (https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf) for germline biomarker testing if they have:
- A known pathogenic germline variant in their family
- Metastatic prostate cancer
- Intermediate-risk (Gleason 7 or higher) prostate cancer
- Intraductal- or cribriform-pathology prostate cancer
Germline biomarker testing typically includes multiple genes found on multigene testing panels and also considers family history of breast, pancreatic, ovarian, melanoma, and other cancers.
The Northern European founder pathogenic variant, HOXB13 G84E, is the most studied HOXB13 variant. It is strongly correlated with an increased lifetime risk of developing prostate cancer (https://doi.org/10.1016/j.ctrv.2019.101927) (three to five times higher than the general population, which is 12.5% (https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html)) and poorer prognosis (https://doi.org/10.1016/j.ctrv.2019.101927), with a higher prostate-specific antigen at diagnosis, Gleason score, and incidence of positive surgical margins in radical prostatectomy specimens.
In January 2022, the U.S. Food and Drug Administration approved adding HOXB13 G84E to the direct-to-consumer test 23andMe (https://www.accessdata.fda.gov/cdrh_docs/pdf21/K211499.pdf) as a prostate cancer risk panel. It is the only variant on the panel and does not represent comprehensive germline biomarker testing for prostate cancer. Because consumer tests are readily available, patients may approach their oncology nurses with results and ask for guidance. Nurses should refer them to a genetics professional to determine whether they require additional or confirmatory testing, obtain recommendations for care based on a comprehensive risk assessment, and, if indicated, begin cascade testing for family members potentially at risk.
Prevention and Early Detection
Nurses have an important role in preventing prostate cancer in high-risk individuals or facilitating early detection. Assess both newly diagnosed patients and long-term survivors for red flags of hereditary risk, and familiarize yourself with the National Comprehensive Cancer Network guidelines (https://www.nccn.org/)’ recommendations for germline biomarker testing in prostate cancer. Instruct patients with a pathogenic HOXB13 variant on the importance of annual prostate cancer screening (https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2022.html) with a digital rectal examination and prostate-specific antigen biomarker beginning at age 40.
As knowledge about the HOXB13 gene’s significance evolves, review each patient’s screening recommendations every 12–18 months and update as needed to reflect new evidence or personal and family medical history.