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Mutation provides insight into genetic cause of familial prostate cancer
Ewing CM. N Engl J Med. 2012;366:141-149.
Men with familial prostate cancer were more likely to carry a mutation in the 17q21-22 region than men with nonfamilial prostate cancer, recent results suggested.
Researchers from several sites in the United States aimed to further investigate previous findings suggesting that chromosome 17q21-22 may be linked to prostate cancer susceptibility. They screened more than 200 genes in the 17q21-22 region.
Families with links to the possible region were selected for screening. The final analysis involved sequencing germline DNA from 94 unrelated patients with prostate cancer, their family members, additional control participants and controls to characterize the frequency of the identified mutations.
A rare but recurrent mutation, G84E, was discovered in HOXB13 (rs138213197) in probands from four families in the analysis. The gene is a homeobox transcription factor gene that is vital to the development of the prostate. The mutation was discovered in all 18 men with prostate cancer from these families.
Among 5,083 unrelated patients with prostate cancer of European descent, the carrier rate for the G84E mutation was increased by a factor of approximately 20. The rate among prostate cancer patients was 1.4% vs. a rate of 0.1% among controls without prostate cancer (P=8.5310<−7).
Men with early-onset, familial prostate cancer carried the mutation at a rate of 3.1% vs. a 0.6% rate among men with late-onset, nonfamilial prostate cancer (P=2310−6).
“Although the variant accounts for a small fraction of all prostate cancers, this finding has implications for prostate-cancer risk assessment and may provide new mechanistic insights into this common cancer,” the researchers wrote.
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The recent publication by Ewing and colleagues is important on many levels. First, this work demonstrates clearly that for a small number of men with prostate cancer — particularly those men with “early onset” and hereditary disease — a specific mutation (G84E) in the HOXB13 gene appears to play a causative role. Second, for a very small number of men with apparently non familial/”routine” prostate cancer, other HOXB13 mutations are present. These data impute an important role in the pathogenesis and perhaps progression of this AR–interacting transcription factor, a role whose precise mechanism currently is undefined but is likely to be delineated soon. This work also demonstrates the complexity of the genetic mechanisms of this common cancer and, by inference, most other cancers. It seems likely that delineation of pathogenic and potentially “targetable” mutations will require very careful dissection of genomic information and that we will subsequently divide patients into smaller and smaller subgroups based on these data. Such subgroup allocation based on individual tumor genomics will provide substantive approaches to improve screening, prevention and treatment paradigms. This is very exciting work and a fascinating time to be an oncologist.
– Donald L. Trump, MD, FACP
HemOnc Today Editorial Board member
Disclosure: Dr. Trump reports no relevant financial disclosures.
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