Rare G84E mutation strongly associated with familial (inherited) prostate cancer


A new study has confirmed an initial finding that the rare G84E mutation (also known as rs138213197) in the HOXB13 gene is a significant driver of risk for prostate cancer among men with a family history of the disease.

The abstract of the paper by Akbari et al. confirming this finding is available on line in the Journal of the National Cancer Institute; additional information is available in a commentary on the Medcape Oncology web site. The original article by Ewing et al. demonstrating the existence of this mutation among men with apparently hereditary prostate cancer was published in the New England Journal of Medicine in January this year.

The bottom line appears to be this:

  • The G84E mutuation is found in < 1.5 percent of all men with prostate cancer.
  • The mutation is exclusive to Caucasian males and has not (so far) been observed in any men of African ancestry.
  • The mutation is  found in about 1.0 to 3.0 percent of  men with early-onset, familial prostate cancer but in about 0.5 percent (or less) of men with late-onset, non-familial prostate cancer.

Akbari et al. were able to confirm the initial finding by sequencing the DNA from 1,843 men diagnosed with prostate cancer (case subjects) and 2,225 men without prostate cancer (control subjects) and looking for mutations in the HOXB13 gene. All of the patients were between 40 and 94 years of age and had undergone a prostate biopsy at one of two tertiary care centers in Canada. (One does wonder why any man of 94 was having a prostate biopsy, but that’s a different question.)

They found that:

  • 12/4,068 men (0.3 percent) carried the G84E mutation.
  • 10/1,525 white males with prostate cancer (0.7 percent) carried the mutation.
  • 2/1,757 white males without identifiable prostate cancer (0.1 percent) carried the mutation.
  • The presence of the mutation was associated with a significantly increased risk for prostate cancer (odds ratio = 5.8 percent).

The original paper by Ewing et al. had reported that:

  • 72/5,083 white males with prostate cancer (1.4 percent) carried the mutation.
  • 1/1,401 white males without identifiable prostate cancer (0.1 percent) carried the mutation.
  • The mutation was more common in men with early-onset, familial prostate cancer (3.1 percent) than in men with late-onset, non-familial prostate cancer (0.6 percent).

Researchers are hopeful that it will be possible to develop a test that is specific for this mutation that can be used to test men with a family history of prostate cancer. However, the existence of such a test will raise new questions about the diagnosis and treatment of prostate cancer:

  • What is a sufficient family history to justify the use of the test?
  • Is carrying the mutation, on its own, a guarantee of clinically significant prostate cancer?
  • If carrying this gene alone is not a guarantee of clinically significant prostate cancer, then what does one do with this information?

The studies carried out to date suggest that carrying the mutated gene may be very important among a subset of men with a family history of early-onset prostate cancer but have not really addressed the association between aggressiveness of disease and the presence of the mutation. The original identification of this gene mutation was the result of intensive study among male members of four families with a very high risk for early onset prostate cancer.

One Response

  1. This research is a reminder that building an understanding of the genetics behind prostate cancer is slow, tedious, step-by-step work, but that understanding is steadily expanding.

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