The CHEK2 gene (Checkpoint Kinase 2) is a tumor suppressor gene that helps maintain genomic stability. Its normal function prevents the uncontrolled cell growth characteristic of cancer. The protein produced by CHEK2 monitors the integrity of the cell’s DNA. When working correctly, it directs the cell to repair damage or stop dividing, protecting the body from potential malignancy.
The CHEK2 Gene’s Normal Role in Cell Health
The CHEK2 gene encodes a protein that functions as a serine-threonine kinase, an enzyme that modifies other proteins. This protein activates when the cell detects double-strand breaks in its DNA, often caused by radiation or replication errors. Once active, the CHEK2 protein initiates a cell cycle checkpoint, temporarily halting the cell’s division cycle. This pause allows the DNA repair machinery time to correct the damage.
The CHEK2 protein stops cell division by modifying several targets. For example, it stabilizes the p53 tumor suppressor protein and inhibits the CDC25 family of phosphatases, preventing the cell from entering mitosis. This delay ensures that damaged DNA is not replicated. If the DNA damage is too severe to be repaired, CHEK2 signals the cell to undergo apoptosis (programmed cell death), preventing the damaged cell from becoming cancerous.
Understanding CHEK2 Pathogenic Variants and Cancer Risk
A pathogenic variant, or mutation, in the CHEK2 gene impairs its ability to detect or respond to DNA damage. This loss of function means the cell loses its ability to pause and repair itself effectively, allowing damaged cells to continue dividing and accumulating genetic errors, which significantly increases the risk of cancer development. The CHEK2 gene is classified as a moderate-penetrance cancer susceptibility gene, meaning the risk of developing cancer is elevated compared to the general population, but lower than the risk associated with high-penetrance genes like BRCA1 and BRCA2.
The cancer risk associated with a CHEK2 variant is most pronounced for breast cancer, where the lifetime risk for women can be as high as 30%. The risk level can vary significantly depending on the specific variant and the patient’s family history. In men, a CHEK2 variant is associated with an approximately two-fold increased risk of developing prostate cancer.
One of the most common CHEK2 pathogenic variants is 1100delC, a single-nucleotide deletion that leads to a truncated, non-functional protein. This particular variant is frequently observed in individuals of Northern and Eastern European descent and is strongly associated with the increased breast cancer risk. While CHEK2 variants have historically been linked to colorectal cancer risk, recent large-scale studies have suggested that for many carriers, the lifetime risk for colorectal cancer is not significantly increased over the general population.
Genetic Screening and Counseling
Genetic testing for CHEK2 is typically recommended for individuals who have a strong personal or family history of CHEK2-associated cancers, such as early-onset breast cancer or multiple relatives with breast and prostate cancer. The testing involves a blood or saliva sample, which is analyzed to identify the presence of a pathogenic variant. The decision to pursue testing should be made only after a discussion with a healthcare provider, such as a genetic counselor.
Genetic counseling is necessary both before and after testing. Before testing, a counselor reviews the family history and helps the individual understand the potential results and their implications for medical management. Since CHEK2 variants are inherited in an autosomal dominant pattern, a person with a mutation has a 50% chance of passing it on to each of their children. After a positive result, the counselor helps interpret the specific variant, discusses the risk transmission to family members, and outlines the personalized surveillance and risk management options.
Personalized Surveillance and Risk Management
A positive CHEK2 result prompts the development of a personalized cancer surveillance plan that involves screening protocols starting earlier than those for the general population. For women with a CHEK2 variant, the standard recommendation is to begin annual breast magnetic resonance imaging (MRI) with contrast between the ages of 30 and 35. An annual mammogram is then added to the surveillance plan, typically starting at age 40.
Male carriers are advised to discuss the benefits and limitations of prostate cancer screening with their doctor, often including an annual Prostate Specific Antigen (PSA) test starting at age 40. The need for additional screening for other cancers, such as colorectal cancer, is determined by the individual’s family history, as the CHEK2 variant alone may not warrant earlier screening. Risk reduction options may include chemoprevention with medications that can lower breast cancer risk, or in select cases where the lifetime risk remains high, a prophylactic mastectomy may be considered.