What is the Polygenic Risk Score?

Definition SNP and polygenic risk score

In humans, 99.9% of DNA building blocks are the same, but a SNP (single nucleotide polymorphism, pronounced ‘SNIP’) is a unique building block. It is these SNPs that make us look unique and differentiate us from each other, but they can also be linked to an increased risk of certain diseases such as breast cancer. Unlike the well-known breast cancer genes BRCA1 and BRCA 2, which are very rare in the population but confer a significant lifetime risk of breast cancer of up to 60-90% if present, SNPs are much more common in the general population and each SNP confers a small increase in breast cancer risk.

Researchers identify SNPs associated with complex diseases by comparing the genomes of individuals with and without these diseases. The huge amount of genomic data now available allows researchers to identify which SNPs are more common in groups of people with a given disease. There may be a few dozen, hundreds or even thousands of SNPs linked to the risk of a disease. In breast cancer, a few hundred SNPs have been identified so far.

Once identified, the SNPs associated with the risk of developing a disease are then combined into a Polygenic Risk Score (PRS), which reflects the genetic risk of the individual.

How is a PRS obtained?

SNPs are analysed in a genetics laboratory, usually from a saliva sample. The SNPs analysed are then combined using a statistical formula to obtain the SRP, which is presented as a numerical figure. The PRS indicates how a person’s risk compares to that of others with a different genetic make-up.

For example: Anne has a PRS score of 1.0; Mary has a PRS of 2.0; and Justine has a PRS of 0.5. Anne has no particular excess risk because her PRS is 1.0. This is the reference value of the SRP. On the other hand, Marie’s risk is multiplied by 2. As for Justine, she has a PRS score of less than 1, her risk of developing the disease is reduced and divided by 2.

Clinical utility of the polygenic risk score in breast cancer

The PRS is then combined with a clinical data questionnaire to provide an absolute risk of developing breast cancer over a 5-10 year period, which should allow women to be stratified into different risk levels and screening tests to be tailored to detect the tumour as early as possible should it occur.

Understanding how polygenic risk scores can impact on prevention and screening is a very active area of research today.

Private companies such as Predilife in France and Genetype in the US are already offering tests incorporating PRS to predict breast cancer risk in women in the general population and to help physicians guide follow-up screening decisions for their patients.

PRS and family history of breast cancer

The latest studies in breast cancer show that the SRP is relatively independent of family history and is not directly transmitted. It is personal and must be assessed for each individual.