Polygenic Risk in Breast Cancer: New Perspective in Risk Assessment

Breast cancer is the most commonly diagnosed cancer and one of the leading causes of mortality in women worldwide, with a high incidence in both Europe and Latin America. There is extensive scientific evidence about the impact of genetics on the risk of developing this type of cancer.

Mutations in the BRCA1 and BRCA2 genes are associated with a large percentage of cases of hereditary breast cancer, but there are other genes that can also increase the risk. Despite the impact of inherited variants, they are responsible for only 5-10% of breast cancer cases. In addition to monogenic risk assessment, it is now possible to additionally assess polygenic risk by studying thousands of common variants across the entire genome.

The polygenic risk score allows the evaluation of a type of risk that until now went unnoticed and emerges as a relevant tool to assess more accurately the risk of developing breast cancer.

What is Polygenic Risk?

The influence of the genetic component in diseases such as breast cancer can be divided into two main categories: monogenic and polygenic risk. Monogenic risk refers to mutations in a gene such as BRCA1 and BRCA2 where a single variant implies an elevated risk of developing the disease. On the other hand, polygenic risk involves the sum of the effect of small common genetic variants, known as single nucleotide polymorphisms (SNPs). These variants, although alone have limited impact, together can significantly influence susceptibility to breast cancer.

As we discussed in our blog article "What is the Polygenic Risk Score or PRS (Polygenic RiskScore)”, the PRS assesses the cumulative risk of an individual by analyzing hundreds, thousands or millions of polymorphisms identified from data obtained from GWAS (Genome-wide Association Studies) studies. Using statistical algorithms that take into account the sum of the variants and their frequencies, a score is assigned that reflects the probability of developing the disease. In the case of breast cancer, several GWAS studies have identified from 300 to more than 500,000 SNPs that are associated with the risk of developing the disease.

This tool allows a more accurate assessment of risk, especially in women who do not have mutations, but is a promising tool for cases with mutations in moderate penetrance genes associated with breast cancer.

Impact on Breast Cancer Risk Assessment

The inclusion of PRS in breast cancer risk assessment has emerged as a high-impact strategy for the early detection of this pathology, for which screening strategies exist. Some advantages of the clinical implementation of this test are:

• More complete breast cancer risk assessment: by integrating monogenic and polygenic risk it is possible to identify a larger number of patients at risk, improving breast cancer screening. This is especially useful in families with a history of breast cancer in which hereditary mutations have not been detected.
• Identification of a greater number of women at risk: polygenic risk assessment allows the identification of sporadic cases at increased risk, detecting women who were previously unidentified.
• Research: PRS is driving new research into the biological mechanisms underlying breast cancer and facilitating the development of risk stratification tools in women with moderate penetrance mutations.

Monogenic vs. polygenic risk study

Although both tests are based on genetic studies, the approaches are different and, in fact, complementary. A woman may have an inherited mutation associated with breast cancer risk and have normal polygenic risk, or conversely, she may have an elevated risk PRS in the absence of mutations. For a more complete assessment of the patient's risk, the combination of both screening strategies is the best option, but they can also be evaluated independently.

Clinical Application of Polygenic Risk

Currently, breast cancer risk calculators allow the integration of all the patient's clinical information to obtain an overall estimate of risk that allows the specialist to make decisions about the management and follow-up of the patient.

Many specialists already incorporate the use of these calculators in their clinical practice, and today there are advanced calculators such as CanRisk based on the Boadicea study, which allow the inclusion of monogenic and polygenic risk information together with the rest of the patient's clinical information available, notably improving the risk calculation.

The application of the Polygenic Risk Score is becoming increasingly widespread in clinical practice. In European countries such as the UK, the PRS is already part of breast cancer risk assessment programs.

PRS has the potential to revolutionize breast cancer prevention, offering a more individualized approach to risk prediction, providing the physician and patient with a new tool for early detection and prevention of this disease.

Veritas offers myHealthScore, the polygenic risk genetic test with which we can know if we have a high risk of presenting different multifactorial diseases such as breast cancer, prostate cancer, diabetes and cardiovascular pathologies, thanks to the study of millions of variants scattered throughout the genome. If you want more information, do not hesitate to contact us.