Polygenic risk prediction: The clinical significance


Session type:

Paul Pharoah
University of Cambridge, UK


Genome-wide association studies and large-scale replication have identified many susceptibility alleles for the common cancers. The clinical relevance of these findings have been widely questioned and genetic testing for common susceptibility alleles has not yet entered routine clinical practice. However, the number of risk alleles for some of the common cancers may now be sufficient to provide useful risk discrimination.

For example, sixty-four loci associated with an increased risk of breast cancer have now been identified. The risks associated with any one of these alleles are modest, but together, particularly when combined with established lifestyle risk factors, they may identify high-risk and low-risk sub-groups of the population that are sufficiently different to warrant personalised disease prevention based on risk. The 5 percent of the population at highest risk would have a lifetime risk of breast cancer of 15 percent or more, compared to the 5 percent of the population at lowest risk who have a lifetime of less than 4 percent. It has been shown that a personalised breast cancer screening programme based on age and polygenic risk would reduce the number of women undergoing screening without reducing the number of screen detectable cases. This would not only reduce the costs of screening (fewer screening examinations), but might also reduce the harms associated with screening such as false positives, over diagnosis and overtreatment.

An even greater number of risk alleles have been identified for prostate cancer. The NHS does not currently offer prostate cancer screening because the harms of PSA testing are thought to outweigh the benefits. As with breast cancer, polygenic risk prediction offers the potential for targeting screening at those at highest risk, for whom the benefits may outweigh the harms.