The HOXB13 gene is associated with an increased risk for autosomal dominant prostate cancer. The HOXB13 c.251G>A (p.Gly84Glu) variant is observed more frequently in males with prostate cancer compared to healthy controls (PMID: 22236224, 23064873, 26517352, 26108461, 25629170, 25595936, 24026887).
The HOXB13 gene, which encodes a transcription factor, one of the homeobox protein family, acts as a tumor suppressor and is thought to play a role in the development and maintenance of the skin.
Prostate cancer is one of the most common types of cancer diagnosed in men. Hereditary prostate cancer accounts for approximately 5-10% of all prostate cancer. It is defined by the occurrence of prostate cancer in at least three men in a nuclear family, prostate cancer affecting three generations in a family, or two relatives diagnosed before age 56 (PMID: 26176944).
Numerous studies have shown that the c.251G>A (p.Gly84Glu) variant in HOXB13, also known as G84E, is associated with an increased risk of prostate cancer (PMID: 26176944, 23457453, 22236224, 23064873, 22841674, 26517352, 23518396, 26108461, 25629170, 25595936, 24026887). This variant is associated with earlier-onset diagnosis (<55 years) and individuals with this variant are more likely to have a positive family history of prostate cancer (PMID: 23292082, 22236224, 24026887, 26108461, 25595936, 23396964).
Large case control studies and meta-analysis across studies demonstrated that men with this variant have approximately a 33-60% lifetime risk of prostate cancer compared to the general population risk of 12% (PMID: 22841674, 23457453, 25595936, 26517352, 24026887). Additionally, this variant is present in 0.2% of the general population (Exome Aggregation Consortium (ExAC). Accessed September 2016). The G84E variant is observed at a higher frequency in individuals of European ancestry (0.8%), suggesting it may be a European founder mutation (PMID: 22841674). An individual with this variant will not necessarily develop cancer in his lifetime, but the risk is increased over the general population risk. There may also be an increased risk for other cancer types, however, the current evidence is limited and conflicting (PMID: 22853031, 23099437, 23292082, 25629170, 26517352).
HOXB13 is a tumor suppressor gene that encodes a transcription factor that is part of the homeobox protein family ( National Library of Medicine. Genetics Home Reference. HOXB13. Accessed September 2016). HOXB13 plays a role in embryonic growth and development, and is particularly expressed in the prostate, where it interacts with androgen receptors (PMID: 25629170, 22236224).
Hereditary predisposition to cancer due to the HOXB13 G84E variant has autosomal dominant inheritance. This means that an individual with this variant has a 50% chance of passing it to their offspring. Once such a variant is detected, it is possible to identify at-risk relatives who can pursue testing. Many cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it).
The National Comprehensive Cancer Network® (NCCN) currently does not recommend additional prostate cancer screening for individuals with the HOXB13 G84E variant beyond what is recommended for the general population. However, NCCN cautions that cancer screening should ultimately be guided by personal and family history (The National Comprehensive Cancer Network® (NCCN). Prostate Cancer Early Detection. Version 1. 2016). In the absence of formal guidelines, a formal urology consultation may be considered.
An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.
Even though data regarding HOXB13 is limited, knowing if the G84E variant is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding HOXB13 are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow standard screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.
Review date: September 2016
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*HOXB13: Analysis is limited to the NM_006361.5:c.251G>A, p.Gly84Glu variant.