A gene is a specific set of instructions that guides how our bodies grow and function. A gene mutation is a change in those instructions, which can alter how a particular process works. One such gene is PALB2, and a mutation within it can have implications for a person’s long-term health.
The Role of the PALB2 Gene
The PALB2 gene, which stands for “Partner and Localizer of BRCA2,” is a tumor suppressor gene. Tumor suppressor genes act like a car’s braking system, preventing cells from growing and dividing too rapidly or in an uncontrolled way. The PALB2 gene performs this function by helping to repair damaged DNA.
Our cells experience DNA damage daily from environmental exposures or normal metabolic processes. The PALB2 gene produces a protein that is a component of the machinery that fixes these breaks, specifically a type of damage called double-strand breaks. It acts as a partner to the well-known BRCA2 gene, helping to recruit it to the site of DNA damage. This interaction is necessary for a high-fidelity repair process called homologous recombination, which ensures that DNA breaks are mended accurately.
This function is part of a network of proteins dedicated to preserving genome integrity. The role of PALB2 as a stabilizing partner for BRCA2 is so intertwined that cells deficient in PALB2 show reduced levels of the BRCA2 protein. This cooperative effort is a process for suppressing tumor development.
Associated Cancer Risks
A pathogenic mutation in the PALB2 gene impairs its ability to repair DNA, increasing the lifetime risk of developing certain cancers. For women, the primary risk is for breast cancer, with lifetime estimates ranging from 35% to 63%. This compares to an approximate 12% lifetime risk for women in the general population. The risk level is considered comparable to that associated with BRCA2 mutations.
The risks extend to other cancers as well. The lifetime risk for ovarian cancer for a female carrier is estimated to be around 3% to 5%, higher than the 1-2% risk in the general population. Both men and women with a PALB2 mutation face an increased lifetime risk of pancreatic cancer, estimated at 2% to 5%, compared to less than 2% for the general population.
Men with a PALB2 mutation also face specific cancer risks. The lifetime risk of male breast cancer is approximately 1%, compared to 0.1% in the general male population. Studies also suggest that PALB2 mutations may increase the risk for prostate cancer above the general population’s 12% lifetime risk. These percentages are estimates, and an individual’s risk can be influenced by their family history of cancer.
Inheritance and Genetic Testing
PALB2 mutations are passed down in a pattern called autosomal dominant inheritance. This means a person only needs to inherit one copy of the mutated gene from one parent to have increased cancer risks. Each child of a carrier has a 50% chance of inheriting the mutation, and both males and females can pass it on.
Genetic testing can identify individuals who carry a PALB2 mutation. Testing is recommended for those with a strong personal or family history of associated cancers. This includes breast, ovarian, pancreatic, or male breast cancer, especially with early-age diagnoses or multiple affected relatives on one side of the family.
Genetic testing is performed using a multi-gene panel that analyzes several cancer susceptibility genes at once, including PALB2, BRCA1, and BRCA2. Since widespread PALB2 testing became more common after 2014, individuals tested before then may not have been screened for this gene and might consider updated testing. A positive result provides information for the individual and their relatives, who may then choose to be tested.
Medical Management and Screening Guidelines
Individuals who test positive for a PALB2 mutation are recommended specific medical management strategies to address the increased cancer risks. The main focus is enhanced surveillance to detect cancers at an earlier, more treatable stage. For women, this involves starting breast cancer screening at a younger age, with guidelines recommending annual mammograms and breast MRIs beginning at age 30.
Risk-reducing surgeries are another option. A prophylactic mastectomy, the surgical removal of the breasts, can lower the risk of developing breast cancer. A risk-reducing salpingo-oophorectomy, the removal of the ovaries and fallopian tubes, may be considered for women after childbearing is complete to lower ovarian cancer risk. The decision to undergo these procedures is personal and made after discussions with a healthcare team.
A PALB2 mutation can also influence cancer treatment. Cancers caused by these mutations result from faulty DNA repair, a weakness that can be exploited by certain drugs. Targeted therapies known as PARP inhibitors are effective against cancers with this genetic signature. These medications work by blocking a different DNA repair pathway, causing the cancer cells to die, making them a treatment option for advanced breast, ovarian, and pancreatic cancers in carriers.