The CHEK2 gene is a moderate-penetrance tumor suppressor gene that plays a significant role in hereditary cancer risk, particularly for breast cancer. The 1100delC variant is a common mutation strongly associated with an increased lifetime risk of developing certain cancers. This variant involves deleting a single cytosine base pair at position 1100, which creates a premature stop codon. This results in a non-functional protein that cannot perform its normal functions, increasing an individual’s susceptibility to cancer.
The Function of the CHEK2 Gene
The CHEK2 gene (Checkpoint Kinase 2) is a caretaker gene that helps maintain the stability of the genome. Its function is to produce a protein kinase that acts as a sensor and responder to DNA damage within the cell. When DNA is broken or damaged, the CHEK2 protein activates and initiates cellular responses to prevent the creation of a cancerous cell.
The primary actions of the functioning CHEK2 protein are to halt the cell cycle, allowing time for DNA repair, or to initiate programmed cell death (apoptosis) if the damage is too extensive. This ensures that cells with potentially cancer-causing mutations do not divide. The 1100delC mutation disrupts this process by creating a truncated, non-functional CHEK2 protein. This loss of function means DNA damage can go unrepaired, increasing the likelihood of cancer developing.
Cancer Risks Associated with 1100delC
Inheriting the CHEK2 1100delC variant confers an elevated, moderate risk for several types of cancer, especially compared to high-penetrance genes like BRCA1 and BRCA2. The most significant risk is for female breast cancer. The lifetime risk for a woman carrying one copy of the variant is estimated to be 23% to 27%, compared to a general population risk of about 12.5%. This represents approximately a two- to three-fold increased risk compared to non-carriers.
The increased risk is often higher for women diagnosed at a younger age, suggesting a stronger genetic influence in early-onset cases. Women previously diagnosed with breast cancer who carry the variant also face an increased risk of developing a second primary breast cancer in the opposite breast. Men who inherit the 1100delC variant face an increased risk for male breast cancer, which is rare in the general population, with a risk ratio approximately three-fold higher than non-carriers.
Beyond breast cancer, the 1100delC variant is associated with elevated risks for prostate and colorectal cancer, though data is less consistent. For prostate cancer, the variant confers an increased risk, with some studies suggesting a hazard ratio around two-fold higher than the general population. This risk is particularly relevant for men with a strong family history of the disease. For colorectal cancer, the association is less definitive; some studies find a modest increase in risk, while others, including national guidelines, indicate no increased risk.
Understanding Genetic Inheritance
The CHEK2 1100delC variant is inherited in an autosomal dominant pattern. This means an individual only needs to inherit one copy of the altered gene to have an increased cancer risk, classifying them as heterozygous. If a parent is a carrier, their offspring have a 50% chance of inheriting the altered gene.
This inheritance pattern means first-degree relatives, such as siblings, also have a 50% chance of being carriers. Genetic testing of at-risk family members is often recommended to identify those who may benefit from enhanced cancer surveillance. Inheriting two copies of the variant (homozygous or biallelic state) is significantly rarer. This state is associated with a much higher lifetime risk of breast cancer, potentially up to six-fold, compared to inheriting just one copy.
Medical Monitoring and Prevention Strategies
Carriers of the CHEK2 1100delC variant are advised to adopt enhanced medical monitoring protocols tailored to their specific risks. For women, this involves starting breast cancer screening earlier and incorporating more sensitive imaging techniques. Current guidelines suggest beginning annual mammography screening by age 40, often including the addition of annual breast magnetic resonance imaging (MRI) with contrast.
These enhanced screening methods are often staggered, with a mammogram performed six months after the MRI to ensure comprehensive, year-round surveillance. For men, prostate cancer screening should be considered earlier than the general population, often starting around age 40, especially with a strong family history. This screening typically involves an annual prostate-specific antigen (PSA) blood test.
Due to the potential for increased colorectal cancer risk, individuals with the variant and a personal or family history of colon polyps or cancer may need to begin colonoscopies earlier or more frequently than standard guidelines recommend. Beyond surveillance, risk-reducing options can be discussed with a specialist, such as chemoprevention using medications like tamoxifen to lower breast cancer risk. While risk-reducing mastectomy is not routinely recommended for CHEK2 carriers, it remains an option based on personal risk factors and family history.