More on familial and hereditary risk for prostate cancer


Slowly but surely we are learning more about the roles of family history and familial genetics (heredity) in determining risk for prostate cancer — and most especially risk for clinically significant forms of prostate cancer.

A new paper by Beebe-Dimmer et al., based on data from the Utah Population Database, was used to identify 619,630 men, all aged ≥ 40 years, who were members of a pedigree that included at least three consecutive generations. These 600,000+ men were then all evaluated for a family history of hereditary prostate cancer (HPC), hereditary breast or ovarian cancer (HBOC), and/or Lynch syndrome (LS) — as well as for each individual’s own prostate cancer status.

It should be noted that a strong family history of prostate cancer was defined in this study as a man having either three first-degree relatives with prostate cancer or two first- and/or second-degree relatives with early-onset prostate cancer.

Here are some of the key findings from this study:

  • Prostate cancer cases totaled 36,360
  • These 36,360 cases were classified into one or more subtypes:
    • Early onset
    • Lethal
    • Clinically significant
  • Relative risk (RR) for all subtypes of prostate cancer based on family history were found to be
    • HPC (RR = 2.30)
    • HBOC (RR > 1 but < 2)
    • LS (RR > 1 but < 2)
  • The highest relative risk level associated with family history was seen to occur for early onset prostate cancer in all pedigree types (which is consistent with the contribution of genetic factors to disease occurrence).

The authors conclude that:

In this large, population-based, family database, the risk of [prostate cancer] varied by cancer [family history] and was most strongly associated with [early onset] disease. These results are critically valuable in understanding and targeting high-risk populations that would benefit from genetic screening and enhanced surveillance.

Your sitemaster was recently asked (by a very knowledgeable patient) whether we had data yet to confirm whether genetic testing of persons with a family history of prostate cancer could actually lead to a decrease in projected risk. Specifically, your sitemaster’s correpondent asked the following:

  • Do you know of any studies, where they looked at the risk of family history in cases, where germline tests for mutations in one of the … genes (BRCA2, etc.) were negative?
  • In other words, is the family history a risk factor only in combination with one of these germline mutations?

The potential implication, of course, is that a negative germline test could potentially take away some of the fear for brothers and sons of prostate cancer patients.

The problem, as your sitemaster currently understands this, is that while there are certain germline mutations that come with a relatively high level of risk for prostate cancer (e.g., the BRCA2 mutation), we now know of a vast spectrum of mutations (germline and somatic) that have been associated with risk for prostate cancer. What we don’t know yet is which of these germline mutations (i.e., the hereditary mutations) should be tested for on a regular basis. Nor do we know whether there might be important and as yet unidentified germline mutations that are associated with risk for prostate cancer.

Thus, if one was able to “rule out” the familial mutations that are currently known to be associated with a family history of the disease, it might lower the fear level for other family members to some degree, but it can’t (yet) do so with any real degree of certainty.

 

3 Responses

  1. What do you know about the HSD3B1(1245C) variant? Recent articles point out, interestingly, that men with this polymorphism respond poorly to ADT (1) but respond very well to abiraterone (2).
    (1) https://newsroom.clevelandclinic.org/2020/02/13/cleveland-clinic-researchers-validate-link-between-genetic-variant-and-poor-outcomes-in-men-with-advanced-prostate-cancer/
    (2) https://pubmed.ncbi.nlm.nih.gov/30794306/

  2. Dear Ethan:

    Your sitemaster does not claim any high level of expertise on the specific variants of particular (relatively rare) mutations that are associated with some forms of prostate cancer. Questions like yours need to be addressed to a specialist in the genetics of prostate cancer and/or to a genetic counselor.

  3. For the longest time, we have recognized that family history of hormonal cancers places a man at higher risk for prostate cancer — and vice versa … that offspring can be more at risk for certain hormonal cancers.

    We know that a smallish percentage of men carry BRCA1– and BRCA2-related gene mutations, and Lynch syndrome but these are not enough to explain the higher familial risk on their own.

    I have been wondering how we explain the balance. Could it be by other mutations that are not fully understood but may be inherited.

    On June 30th, UsTOO and AnCan are presenting a webinar to look at some of the issues bound up with ‘The TALK’ fathers with prostate cancer must have with their kids. For more infomation please click here.

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