A polygenic risk score (PRS) for breast cancer is a tool that estimates an individual’s genetic predisposition to developing the disease. It provides a personalized risk assessment by combining the effects of many common genetic variations. This score quantifies an individual’s genetic risk beyond traditional factors, helping to stratify people into different risk categories.
How a Polygenic Risk Score is Calculated
The foundation for calculating a polygenic risk score lies in large-scale genetic research called Genome-Wide Association Studies (GWAS). These studies analyze the DNA of hundreds of thousands of individuals to identify common genetic variants that are more frequent in people with breast cancer. These variants are Single Nucleotide Polymorphisms (SNPs), which are changes to a single DNA building block. Researchers have identified more than 300 SNPs associated with breast cancer development.
Each SNP has a very small effect on breast cancer risk. The core concept of a PRS is that the cumulative impact of many of these small-effect variants can be substantial. When combined, they become a significant indicator of an individual’s underlying genetic susceptibility.
To generate the score, a person’s DNA from a saliva or blood sample is analyzed to see which risk-associated SNPs they carry. A weighted score is then calculated. The contribution of each SNP is weighted by its effect size, which is a measure of how strongly it is associated with breast cancer. The final score represents the sum of all these weighted risks, providing a single measure of an individual’s inherited risk.
Interpreting the Score and Clinical Application
Interpreting a polygenic risk score involves comparing an individual’s score to the distribution of scores in the general population. This comparison places them into a risk category, such as low, average, or high. A high score indicates a greater inherited predisposition for breast cancer than the average person, while a low score suggests a smaller genetic risk.
The clinical application of a PRS is to refine a woman’s individual breast cancer risk assessment, which then guides management decisions. A woman with a high PRS may be recommended to begin screening at an earlier age or undergo more frequent mammograms. In some cases, clinicians may suggest supplemental screening with a breast MRI for those in the highest risk categories.
These scores are often integrated into existing risk prediction models, such as the Tyrer-Cuzick or BOADICEA models, which also incorporate factors like family history and breast density. Adding a PRS can improve the accuracy of these models. For example, one study showed that incorporating a PRS caused 16% more women to cross the risk threshold that makes them eligible for enhanced screening with MRI.
Beyond screening, a high PRS can initiate conversations about other risk-reducing strategies. This could include discussions about preventative medications, known as chemoprevention, or a more focused emphasis on lifestyle modifications like diet and exercise.
Differentiating Polygenic and Monogenic Risk
The genetic component of breast cancer risk can be divided into two categories: polygenic and monogenic. The distinction between them lies in the number of genes involved and the magnitude of their effect on risk.
Monogenic risk refers to the risk conferred by a mutation in a single gene. These mutations, such as those in the BRCA1 and BRCA2 genes, are rare but have a high impact. A pathogenic variant in one of these genes can dramatically increase a person’s lifetime risk of developing breast cancer, sometimes up to 76% for BRCA1 carriers by age 70. These high-penetrance genes are responsible for about 5-10% of all breast cancer cases.
Polygenic risk arises from the combined effects of hundreds of common, low-impact genetic variants. Each SNP contributes only a small amount to the overall risk, and it is their cumulative effect that becomes meaningful. This type of risk is more common throughout the population and accounts for a larger portion of the inherited component of breast cancer.
The two types of tests assess different aspects of inherited risk and are complementary. An individual can have a high polygenic risk score without carrying a high-risk monogenic mutation like BRCA1 or BRCA2, and vice versa. For a comprehensive risk assessment, both can be used together to provide a more complete picture of a person’s genetic susceptibility.
Limitations and Considerations
A significant limitation of current polygenic risk scores is their reduced accuracy for individuals of non-European ancestry. The vast majority of the GWAS used to develop these scores have been conducted in populations of European descent. This means the risk estimates are most reliable for this group and may be less accurate when applied to people of African, Asian, or other ancestries.
It is also important to recognize that a PRS provides a measure of probability, not a definitive diagnosis. A high score does not mean an individual will develop breast cancer, nor does a low score guarantee they will not. The score is one piece of a larger puzzle.
The score does not account for all known breast cancer risk factors. Non-genetic factors such as lifestyle choices, environmental exposures, and mammographic breast density play a substantial role in determining a person’s ultimate risk. A PRS should be considered alongside these other elements for a holistic risk evaluation.