Breast Cancer: Beyond BRCA1 and BRCA2

Although most tumors are sporadic, a clinically significant percentage (between 5-10%) develop on the basis of an inherited genetic predisposition. Identifying the presence of germline variants related to this type of cancer allows us to redefine clinical management, not only for the patient, but for their entire family. In our article, “Genetics of Hereditary Cancer,” we delve into the characteristics that define this type of cancer.

In relation to hereditary breast cancer, the best-known genes are undoubtedly BRCA1 and BRCA2. Since Dr. Mary-Claire King identified their relationship with this type of cancer in the 1990s, research and diagnosis of hereditary breast and ovarian cancer have focused on these genes, as the presence of pathogenic variants is associated with a very high risk of developing it.

It has been observed that BRCA1/2 genes account for only 25% of hereditary breast and ovarian cancer cases, so limiting testing to these genes may overlook some patients at risk. This gap in diagnosis prompted the search for other genes that would allow for a more comprehensive assessment of the risk of this type of cancer. Thanks to technologies such as NGS (Next Generation Sequencing), we can simultaneously study a large number of genes. This allows us to address the key question: what happens when a BRCA1/2 test is negative but family history still suggests a genetic component?

BRCA1, BRCA2, and PALB2: High-risk genes

This category includes high-penetrance genes, in which the presence of pathogenic variants confers a risk of developing breast cancer that is five times higher than that of the general population. Within this group, BRCA1 and BRCA2 are the best-known tumor suppressors; their main function is to mediate DNA damage repair, a critical process for preserving genomic integrity. In addition to these two genes, scientific evidence has established PALB2 as a third key gene in this high-risk group.

The function of PALB2 is directly associated with the BRCA1/2 genes, as it also plays a key role in DNA repair. If a variant is present in this gene, this function may be compromised.

Pathogenic variants in PALB2 are clinically significant, as they confer a high risk of breast cancer, almost comparable to that of BRCA2. In quantitative terms, this translates into a lifetime risk for female carriers of between 40% and 60%. Furthermore, its clinical implication is not limited to breast cancer, but is also associated with an increased risk of pancreatic and ovarian cancer.

Given the high associated risk, international clinical guidelines already recommend specific management for carriers of PALB2 variants, similar to that for carriers of BRCA1/2 variants. This follow-up includes more comprehensive screening with annual mammograms and MRIs from an early age.

The contribution of moderate-risk genes

This category includes genes with moderate penetrance that increase the risk of developing breast cancer, generally between 2 and 4 times higher than that of the general population.

ATM

This gene is crucial in the cellular response when DNA damage occurs, functioning as a key activator of repair pathways involving proteins such as BRCA1. Pathogenic variants in ATM are associated with an estimated lifetime risk of breast cancer between 20% and 40% (3-4 times higher than the general population), which justifies adapting clinical follow-up with measures such as recommending annual MRI scans.

CHEK2

Like ATM, the CHEK2 gene plays an important role in DNA repair and cell cycle control. One of its most studied variants occurs most frequently in northern European populations. Pathogenic variants in this gene increase the risk of breast cancer in women by approximately 2 to 3 times compared to the general population, and in men, there could be a substantial increase in the risk of developing both prostate and breast cancer.

The Importance of Multigene Panels

The spectrum of hereditary breast cancer is broad and complex. Limiting testing to the BRCA1 and BRCA2 genes may leave a significant number of families at genetic risk without a diagnosis.

For this reason, the use of multigene panels, which simultaneously analyze these genes and other additional genes with which there may be phenotypic overlap, is becoming standard practice in clinical practice, as many genes are associated with several types of cancer. This strategy has several advantages, such as:

• Maximize diagnostic performance: Provides a much more comprehensive risk assessment.
• Personalize follow-up: Screening recommendations are tailored according to the gene and variants detected, with a better risk estimate.
• Optimize family counseling: Enables a more accurate cascade study for the rest of the family.

In this blog, we have tried to convey the importance of genetic screening related to breast cancer and the inclusion of other genes in addition to the BRCA1 and BRCA2 genes, which allows us to perform a more comprehensive assessment of hereditary breast cancer risk. The request for these tests and the interpretation of the findings must always go hand in hand with expert genetic counseling, which can interpret the results and establish a clear and personalized action plan.

At Veritas, we offer genetic studies based on comprehensive and up-to-date multigene panels, ensuring a thorough assessment of hereditary risk. In addition, we offer the option of adding myPharma, a pharmacogenetic study that allows medical prescriptions to be tailored to avoid adverse effects and improve their effectiveness. We understand that each result must be interpreted in the clinical and family context, which is why genetic counseling is an essential pillar of our process. If you would like more information, please do not hesitate to contact us.