Two new discoveries in the molecular genetics of prostate cancer

Two new papers published late this week address the potential role of specific genetic variations and mutations in the development and progression of clinically significant types of prostate cancer.

The important thing about these papers from a patient perspective is not the detailed science involved, which is complex and largely inscrutable to those without extensive training in biochemistry and molecular biology. Rather, these two papers exemplify our rapidly growing understanding of why some men get (or don’t get) prostate cancer at all and how prostate cancer moves through its biological lifecycle as it progresses into the castration-resistant phases (when it does).

The first of these papers, by FitzGerald et al., published in Cancer Epidemiology, Biomarkers & Prevention, is focused on “germline missense” variants in the BTLN2 gene (properly known as the butyrophilin-like 2 gene).

The authors looked at genetic sequencing data derived from 91 people within 19 families with a history of hereditary prostate cancer and then compared these data to other independent data from another 819 people in a different set of 270 families with hereditary prostate cancer. They were able to show that two rare genetic variants of the BTNL2 gene were very highly associated with risk for prostate cancer in these families. Specifically,

  • Men who carried the BTNL2 mutations in these high-risk families were about 2.5 to 2.7 times more likely to have prostate cancer than men in the general population.
  • Men in these families who did not carry these mutations were usually unaffected by prostate cancer.
  • About 2 percent of all men diagnosed with prostate cancer carry one or other of these two BTNL2 mutations.
  • These mutations appear to be limited to men from families of European ancestry.

Additional information about this study is available in a media release on the web site of the Fred Hutchison Cancer Center in Seattle, Washington.

It is worth noting that, according to that media release, about 42 percent of all forms of prostate cancer are now thought to be a consequence of genetic variations present at birth (i.e., a hereditary component) and that some 5 to 10 percent of those prostate cancer cases are thought to result from rare inherited mutations.

The second paper, by Kai-Hsiung Chang et al., and published in Cell, deals with a mutation known as N367T in an enzyme called 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes a key step in the conversion of an adrenocortical steroid called dehydroepiandrosterone to dihydrotestosterone (DHT) in men who have castration-resistant prostate cancer (CRPC).

The important factor highlighted in this paper is how one particular step in the evolution of late-stage CRPC is facitated by the N367T mutation. Specifically:

  • The 3βHSD1 enzyme catalyzes a rate-limiting step for DHT synthesis in CRPC.
  • Selection for N367T mutant 3βHSD1 occurs in human CRPC tumors.
  • The N367T  mutation in 3βHSD1confers resistance to a biochemical process known as “ubiquitination.”
  • Mutant 3βHSD1 protein accumulates in cells, increasing DHT synthesis and causing CRPC

As the authors point out, conversion of dehydroepiandrosterone to DHT is normally very limited (even in men with localized prostate cancer), but the expression of 367T accelerates this conversion and provides the DHT necessary to activate the androgen recentor. (They also point out that this also means that 3βHSD1 is a valid target for drug therapy that may be valuable in the treatment of CRPC.)

Again, a media release — this time from the Cleveland Clinic — offers a relatively non-scientific background on this particular piece of research.

We have suspected for many years that progression of prostate cancer can be dependent on a whole series of genetic factors over the course of the disease. These two studies provide us with very clear examples of how such genetic factors can occur very early indeed (in certain types of hereditary prostate cancer) or very late in the course of the disease (to lead to aggressive forms of CRPC).

As recently as 20 years ago, our knowledge of the molecular biology and the genetics of prostate cancer was best described as miniscule. Today, we see new discoveries like this on an almlost weekly basis (and it would be utterly impossible for The “New” Prostate Cancer InfoLink to even try to track all of the data now available in this field). However, for clinicians the next trick will be to determine what types of genetic testing should be used at specific points along the clinical pathway may have real value in detertmining when to implement specific types of treatment to stop or at least slow disease progression. It is nlot improbable that we will be close to having a real handle on this issue another 20 years from now.

To give you a really clear example of just how far we have come, when your sitemaster was first introduced to Dr. Judd Moul — now the Chairman of the Scientific Advisory Board of The “New” Prostate Cancer InfoLink (as well as being the Director of the Prostate Cancer Clinic at Duke University Medical Center) — Dr. Moul asked if Dr. Thomas Stamey would be okay with Dr. Moul giving an introductory talk to some urologists about the molecular biology of prostate cancer. Dr. Stamey’s response was that he needed to hear that lecture … even if the rest of the attending urologists weren’t ready for it! It should be noted that, at the time, in 1992, Dr. Stamey was the chairman of the Department of Urology at Stanford University and one of the world’s leading prostate cancer researchers. Dr. Moul was then about to become the first director of the Center for Prostate Research at the Uniformed Services University of the Health Sciences in Bethesda, Maryland.

2 Responses

  1. Thank you for this interesting post. This type of research seems to be on the end of the spectrum opposite the controversy about screening. Hopefully these gentlemen (and gentlewomen) will find not only a scientific answer to the question, “Why me?” but also a way to treat and cure prostate cancer which in this day would be fatal.


    Sitemaster, thank you as always for focusing our attention as survivors on these important developments.

    Regarding the second paper, in Cell, I found the diagram in the link to be helpful. First I had to look up “rate limiting,” and I found a good explanation in Wikipedia at “Structural Biochemistry/Enzyme/Rate-limiting step”. I understand now that the 3βHSD1 enzyme normally slows down the production of DHT via the adrenal gland process. (I’m still not sure what “AMFR” means in the diagram; I’m guessing, based on a search of Wikipedia, that it refers to the “autocrine motility factor receptor” which has to do with ubiquitination, the latter clearly involved in the subject process.)

    Here’s the sentence that caught my attention in your report: ” (They also point out that this also means that 3βHSD1 is a valid target for drug therapy that may be valuable in the treatment of CRPC.)” The important aspect is that addressing the mutation could reduce the amount of DHT produced, thereby reducing fuel for the cancer.

    Other ways of decreasing DHT or its impact have been around for a long time, but, strangely to me, are ignored by many physicians who prescribe hormonal therapy: those tactics are to use 5-alpha-reductase inhibitors (5-ARIs; finasteride/Proscar or dutasteride/Avodart) to block virtually all of the synthesis of DHT from testosterone (not sure of effect on the adrenal precursor route) and/or to block the androgen receptor cancer cell fuel docking ports using an antiandrogen, or using a more recent and advanced drug, including for both old and new drugs typically, bicalutamide/Casodex or flutamide, ketoconazole, or enzalutamide/Xtandi. Abiraterone/Zytiga would also be involved directly or indirectly. My own therapy, which, with recent radiation this spring, has driven my PSA ever downward to 0.07 presently in this fourth round of IADT3 at the 14.5-year point since diagnosis, has involved both an antiandrogen intermittently since 2000 and a 5-ARI continuously since 2000. I find it odd that so many patients still get only single ADT, often with an LHRH agonist such as Lupron, Zoladex, Viadur, or Trelstar, and also strange that their testosterone and DHT levels are not monitored.

    It will be interesting to see how this new discovery impacts the world of ADT therapy.

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