Your genetics can accurately predict your age-related prostate cancer risk

Data from a new study reported in the British Medical Journal discusses a “polygenic hazard score” that can potentially be used to guide screening for aggressive prostate cancer (but only in men of European ancestry at this time).

The newly published paper by Siebert et al. (which is freely available on line as a full-text article) has been written by members of the international PRACTICAL consortium.

The consortium set out to develop and and then validate a genetic tool that would be able to accurately predict age of onset of aggressive prostate cancer and to guide decisions of who to test for prostate cancer risk and at what age. To do this, the research team went through two independent steps.

First, they accessed data from > 31,000 men of European ancestry whose individual, de-identified data are available through the PRACTICAL consortium database. They then used these data to create a polygenic hazard score (PHS) — based on the patients’ genotypes, ages, and cancer-specific information at time of diagnosis and treatment — that was predictive of age-related risk for development of aggressive prostate cancer. The patients’ genotype data included data from 54 different single nucleotide polymorphisms or SNPs.

By “aggressive disease”, the authors mean any form of prostate cancer for which early, definitive treatment (i.e., not active surveillance) would normally be recommended for an otherwise typical healthy man according to guidelines from the National Comprehensive Cancer Network (NCCN). This would include all cancers with any of the following: a Gleason score ≥ 7, a clinical stage of T3-T4, a PSA concentration ≥ 10 ng/ml, nodal metastasis, or distant metastasis.

The idea is that an individual man’s PHS could be used before any decision is made to test him for risk of prostate cancer (e.g., with a PSA or similar test), thereby offering a risk stratification strategy that can maximize the efficiency of prostate cancer screening.

Secondly, the accuracy of the PHS was tested by using data from an independent validation set of > 6,400 of the 80,000+ men initially screened as candidates for enrollment in the ProtecT trial, carried out over the past few years in the United Kingdom.

Using this independent validation set, the research team was able to show the following:

  • The PHS was a very highly significant predictor of age at diagnosis of aggressive cancer (z = 11.2, P < 10−16).
  • When men in the validation set with very high PHS levels were compared with those with average PHS levels, the hazard ratio (HR) for aggressive cancer was 2.9.
  • Inclusion of family history in a combined model did not improve prediction of onset of aggressive prostate cancer (P = 0.59), but …
  • PHS score performance remained high when family history was accounted for.
  • The positive predictive value of PSA screening for aggressive prostate cancer was increased with increasing PHS levels.

Siebert et al. conclude that:

Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive [prostate cancer].

This would appear, at first sight, to offer a major advance in the ability to accurately predict who needs to get tested for risk for aggressive prostate cancer and when. However, there are two major drawbacks to the model as currently developed:

  • First and foremost, it requires all candidates to have had a form of genetic testing that can tell whether they have any one or more of the 54 SNPs used to develop the PHS. Such a test is still relatively expensive at the present time.
  • Second, the current form of the PHS can only be applied with known accuracy to men of European ancestry, thus ruling out all those of African, Asian, and Native American ancestry.

However, … as we increasingly move into the world of personalized health care, and there is an increasingly high probability that large numbers of people will have detailed genetic testing carried out early in their lives as a way to help to know their risks for different disorders over time, what we do have here is proof of a very interesting principle: germline genetic data can be used, in combination with a man’s age, to predict — with considerable accuracy — if and when he should start to be regularly tested for risk for aggressive prostate cancer.

2 Responses

  1. There’s one thing that bothers me about this. We know that not all prostate cancer is explained by inherited genes, so presumably this test has nothing to say about those cancers that arise just from somatic mutations. If we start using this test to decide that some men don’t need to be screened, are we not leaving quite a few men whose cancers are somatic in origin to go undiagnosed? That seems an unacceptable outcome to me. I would love to see someone with a better grasp of statistics than me address this question.

  2. Dear Tom:

    I don’t think that anyone is suggesting or even implying that a test like this be used on its own to project risk for prostate cancer. What a test like this can do is two things: (a) help patients with a family history of prostate cancer have a better understanding of their risk over time (even before there are any signs of actual risk based on PSA) and (b) help patients with an elevated PSA appreciate the level of their risk over time.

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