The BRIP1 gene plays a protective role against cancer by helping maintain the stability of the cell’s genetic blueprint. An inherited mutation in BRIP1 compromises this function, disrupting the body’s natural DNA repair mechanisms. While a mutation does not guarantee cancer development, it significantly increases the lifetime risk for certain malignancies.
The Role of the BRIP1 Gene
The BRIP1 gene is located on chromosome 17 and encodes a protein that acts as a DNA helicase, an enzyme responsible for unwinding DNA strands. This protein ensures the genetic code remains intact and free of errors. It is also known as FANCJ, reflecting its inclusion in the Fanconi Anemia pathway, which handles complex DNA damage.
The BRIP1 protein works closely with other DNA repair proteins, including BRCA1. It is recruited to sites of DNA damage where it interacts with BRCA1 to coordinate complex repair processes. This joint effort fixes serious damage, such as double-strand breaks. When a mutation compromises the BRIP1 protein, its ability to perform this maintenance work is lost.
Inherited BRIP1 Mutations and Associated Cancer Risk
BRIP1 mutations are typically inherited as germline variants, meaning the altered gene is present in every cell, received from one parent. Possessing one mutated copy substantially elevates lifetime cancer risk, though the risk level is moderate compared to high-risk genes like $BRCA1$ and $BRCA2$. The strongest association is with ovarian cancer, including fallopian tube and primary peritoneal cancer.
For women with a pathogenic BRIP1 variant, the estimated lifetime risk for ovarian cancer is approximately 5 to 15%. This is a significant increase over the general population’s average lifetime risk of about 1.1%. Research also suggests a moderately increased risk for breast cancer, sometimes estimated as roughly double that of the general population.
The specific cancer risk varies based on the exact type of mutation and the personal and family history of cancer. Despite being lower than $BRCA1$ or $BRCA2$ risks, the presence of a BRIP1 variant is recognized as a significant factor in hereditary cancer susceptibility.
How BRIP1 Failure Leads to Cancer
The development of cancer begins when the BRIP1 protein loses its ability to perform its normal job. Its main function is to unwind and resolve specific, toxic forms of DNA damage, such as DNA interstrand crosslinks and double-strand breaks. These types of damage prevent the cell from properly replicating its DNA.
When a pathogenic variant renders the protein non-functional, the cell’s quality control system breaks down. The cell attempts repair using less precise, error-prone pathways, resulting in mistakes cemented into the DNA sequence. This accumulation of unrepaired damage and errors is called genomic instability.
Genomic instability increases the rate at which cells acquire new mutations, leading to a cell that has lost its normal growth controls. These accumulating errors drive the cell toward uncontrolled proliferation and tumor formation. This mechanism explains why BRIP1 functions as a tumor suppressor and why its failure initiates carcinogenesis.
Genetic Testing and Identification
Genetic testing for BRIP1 is primarily recommended for individuals with a personal or strong family history of ovarian or breast cancer. It is often included in a multi-gene panel test that checks for several hereditary cancer risk genes simultaneously. Clinicians usually advise testing the family member with a cancer diagnosis first, especially if the cancer occurred at an early age, as this yields the most informative result.
The testing process requires a blood or saliva sample for DNA extraction and analysis. Results categorize the BRIP1 gene status as positive (a pathogenic variant is found), negative (no known pathogenic variant is found), or a Variant of Uncertain Significance (VUS).
A VUS indicates a change in the gene sequence that has not been definitively classified as harmless or disease-causing. VUS results are generally not used for medical decisions due to insufficient scientific evidence regarding clinical significance. Genetic laboratories continuously re-evaluate these variants, and a positive result provides actionable information for a patient’s medical management plan.
Proactive Management of BRIP1 Risk
Individuals who test positive for a BRIP1 pathogenic variant have several proactive strategies to manage their elevated cancer risk. The most definitive action is risk-reducing surgery to address the ovarian cancer risk. Clinical guidelines recommend a risk-reducing bilateral salpingo-oophorectomy (RRBSO)—the surgical removal of the ovaries and fallopian tubes. This is typically performed between the ages of 45 and 50, or earlier based on family history.
For breast cancer risk, management involves following standard surveillance guidelines, which may include enhanced screening based on the patient’s individual history.
Targeted Therapies
BRIP1-associated cancers can benefit from specific targeted therapies. The BRIP1 mutation indicates a defect in the DNA repair pathway, making tumors sensitive to PARP inhibitors. These targeted agents, such as Olaparib, are approved for treating certain BRIP1-associated cancers, including advanced ovarian and metastatic prostate cancer. They work by exploiting the repair defect caused by the gene mutation.