What are genes and genetic variants?
Genes are segments of DNA that provide instructions for producing proteins. Proteins are the building blocks of the body that help it function. Changes in genes are called single-gene variants. Genetic testing can detect different types of these variants. “Pathogenic variants” (also called “mutations”) impact protein function and increase cancer risk. Others, known as variants of uncertain significance (VUS), have unclear impacts on protein function and cancer risk. Determining whether a variant is harmful helps guide treatment and prevention strategies. Identifying pathogenic variants can enable more precise interventions and screenings for individuals and their families.
How much of cancer is hereditary?
While most cancers are sporadic, meaning they occur due to acquired mutations that people accumulate over their lifetime, about 5-10% of cancers are hereditary. There can be clues (or “red flags”) in one’s personal or family history that may suggest a hereditary cause of cancer. Red flags for hereditary cancer syndromes include a family history of multiple relatives with the same or related types of cancer, especially if the cancers occur at younger-than-usual ages.
Early-onset cancer, such as breast or colon cancer diagnosed before age 50, is another warning sign. The presence of rare cancers, such as ovarian or male breast cancer, or individuals with multiple primary cancers (different types of cancer in the same person) also raises suspicion. Additionally, cancers that occur across generations, affecting grandparents, parents, and children, or clusters of certain cancers, like breast and ovarian or colon and endometrial cancer, can signal a hereditary cancer syndrome. Finally, individuals from certain ethnic backgrounds, such as Ashkenazi Jewish heritage, are at higher risk for certain genetic mutations, like BRCA1 or BRCA2 mutations, and should also consider testing. Genetic testing and counseling are recommended for individuals and families exhibiting these patterns.
What are the common genes associated with breast cancer?
The most well-known genes associated with breast cancer are BRCA1 and BRCA2. Mutations in these genes significantly increase the risk of breast and ovarian cancers. Other genes, like TP53, CHEK2, PALB2, and ATM, are also associated with elevated breast cancer risk but may confer moderate or lower risk compared to BRCA mutations. Most cancer-related genes increase the risk for multiple types of cancer, and the specific type of cancer an individual is at risk for depends on which gene is affected.
We can use multi-gene panel testing to analyze multiple genes simultaneously to identify mutations that may increase an individual's risk for various types of cancer. Instead of testing for just one gene, like BRCA1 or BRCA2, multi-gene panels include a broader set of genes associated with different cancers, such as breast, ovarian, colorectal, pancreatic and others. Any pathogenic variants identified on multi-gene panel testing can help guide decisions on cancer screening, prevention strategies (e.g., increased surveillance or preventive surgeries), and even treatment options if a person is already diagnosed with cancer. This information can also be used to test other family members. If an individual has a genetic risk for cancer, their first degree family members (like their siblings or children) are at a 50% risk of having the same pathogenic variant.
What are Polygenic Risk Scores (PRS) in breast cancer and who should get it?
Polygenic risk scores (PRS) is a relatively new tool used in genetics to estimate an individual’s cancer risk based on the cumulative effect of many common genetic variants, each contributing a small amount to the overall risk. Unlike single-gene variants (in genes like BRCA1 or BRCA2 for breast cancer) that can significantly increase disease risk with one single variant, PRS looks at the combined influence of many small genetic differences, each of which contributes only a small amount to the overall risk. These genetic differences, called single nucleotide polymorphisms (SNPs), are scattered throughout the DNA, and while individually they have a minor impact, their collective influence can provide important insights into a person’s predisposition to developing a disease.
In breast cancer risk assessment, PRS can provide a more personalized risk estimate, allowing an individual to have earlier or more frequent cancer screening. Individuals who may consider using PRS for breast cancer risk assessment include those who do not carry high-risk mutations like BRCA1 or BRCA2 but may still have concerns about their breast cancer risk due to family history or other factors.
The integration of PRS into clinical practice is still evolving, but there are genetic testing laboratories that combine multi-gene panel testing with PRS to offer a comprehensive risk assessment.
What is PRS going to tell you that is different from single-gene variant testing?
PRS for breast cancer risk assessment has been in the news recently because of actress Olivia Munn’s story on how PRS changed in her life. She underwent breast cancer screenings with mammograms and breast ultrasounds, and also had genetic testing which were all negative for any concerns. Her OB/GYN then suggested she undergo a PRS test to see if she was higher risk for breast cancer. The test showed that she had a 37% chance of developing breast cancer in her lifetime (compared to the average woman’s risk of around 12%). Her doctor suggested she get a breast MRI, which is typically recommended in people who are higher risk (lifetime risk above 20%). The MRI identified multiple sites of breast cancer and she subsequently was treated with surgery and chemotherapy. She attributes the PRS test that her OB/GYN ordered to what saved her life.
You should talk to your doctor or advanced practice clinician about your personal and family history risk factors for cancer to identify the right approach to assessing your cancer risk and undergoing cancer screening.
What developments are you most excited about related to cancer and genetics?
One of the most exciting developments in genetics is the growing precision in personalized cancer prevention and treatment. The integration of multi-gene panel testing, PRS, and advancements in data interpretation are making it possible to tailor cancer screening, prevention, and even treatment to an individual's genetic risk profile. Additionally, the increasing accessibility and awareness of genetic testing and PRS, driven by public figures like Olivia Munn, is helping more people take control of their health by identifying risks earlier and opting for preventative measures.
