What are other Names for this Condition? (Also known as/Synonyms)

• CHEK2-Associated LFS

What is CHEK2-Associated Li-Fraumeni Syndrome? (Definition/Background Information)

• Li-Fraumeni syndrome (LFS) is a hereditary syndrome causing cancer predisposition; meaning it increases one’s risk for cancer development. LFS is inherited in an autosomal dominant manner. The most common types of cancer found in families with Li-Fraumeni syndrome include, osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, and adrenal cortical tumors
• CHEK2-Associated Li-Fraumeni Syndrome, caused by germline mutations in the CHEK2 gene, is associated with moderately persistent breast cancer. Although, mutations in the CHEK2 gene also appear to be associated with the development of a host of other cancers such as gastric, colon, thyroid, kidney, and prostate cancer, among others
• CHEK2-Associated Li-Fraumeni Syndrome is most commonly found in individuals with a family history of the condition. Developing cancer at a younger age may increase the risk for developing CHEK2-Associated LFS. Certain environmental factors, such as tobacco smoke and radiation exposure, can also increase one’s risk
• The signs and symptoms of CHEK2-Associated Li-Fraumeni Syndrome are related to the malignancies the individual is predisposed to. These include breast cancer, brain/central nervous system tumors, leukemia, colon cancer, or melanoma. CHEK2-Associated LFS can be diagnosed with standard gene sequence testing
• Individuals who develop malignancies from CHEK2-Associated Li-Fraumeni Syndrome are treated for the specific cancer types that arise in them. This may include surgery, chemotherapy, and radiation therapy based on the consideration of the healthcare experts. The prognosis depends on several factors and can vary from one individual to another

Who gets CHEK2-Associated Li-Fraumeni Syndrome? (Age and Sex Distribution)

• It is difficult to estimate the frequency of CHEK2-Associated Li-Fraumeni Syndrome. However, there are likely over 1,000 multigenerational families worldwide with Li-Fraumeni syndrome to date
• There does not appear to be any significant gender predilection for CHEK2-Associated LFS; it can occur in both males and females 
• CHEK2 germline mutations account for around 1-3% of all breast cancer cases in females, and around 4-9% of breast cancer cases in males
• There does not appear to be any ethnic of geographic disparity in the occurrence of the syndrome

What are the Risk Factors for CHEK2-Associated Li-Fraumeni Syndrome? (Predisposing Factors)

The following risk factors are noted for CHEK2-Associated Li-Fraumeni Syndrome: 

• Having a personal history of breast cancer at a younger age without an identifiable mutation in the BRCA1/BRCA2 genes
• A sarcoma diagnosis before the age of 45
• Positive family history of cancer
• Exposure to certain carcinogens including tobacco smoke or radiation exposure

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one's chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of CHEK2-Associated Li-Fraumeni Syndrome? (Etiology)

CHEK2-Associated Li-Fraumeni Syndrome is inherited in an autosomal dominant manner. The risk of passing the altered gene from an affected parent to the offspring is 50% for each pregnancy.

• CHEK2, a tumor-suppressor gene, is located on chromosome 22. Mutations in this gene cause the malfunction of proteins and ultimately disrupt the protein repair pathway. The accumulation of these genetic errors can lead to the development of cancer
• Although most cases of CHEK2-Associated Li-Fraumeni Syndrome are caused by a family history of the condition, some individuals can develop the syndrome spontaneously. The spontaneous (de novo) mutation of the CHEK2 gene is rare but possible for some individuals with CHEK2-Associated LFS 

A related condition, TP53-associated Li-Fraumeni syndrome, is caused by a mutation in the TP53 gene located on chromosome 17. TP53-associated LFS is far more common than CHEK2-Associated LFS.

• Although both conditions can increase the risk for developing cancers, CHEK2-Associated LFS may also lead to the development of thyroid, kidney, and prostate cancers
• Also, unlike in individuals with TP53-Associated LFS, individuals with CHEK2-Associated LFS do not appear to be more sensitive to external carcinogens such as radiation

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of CHEK2-Associated Li-Fraumeni Syndrome?

The following are the possible signs and symptoms associated with CHEK2-Associated Li-Fraumeni Syndrome:

• Thyroid cancer
  • Coughing of blood
  • Difficulty swallowing
• Kidney cancer
  • Low back pain
  • Fatigue
• Breast cancer (lumps in breast/tissue thickening)
  • Bleeding from the nipple
  • Breast pain
  • Inverted nipple
• Colon cancer
  • Persistent change in bowel habits
  • Blood in stool
• Prostate cancer
  • Blood in urine
  • Frequent urination
• Gastric cancer
  • Weight loss
  • Indigestion 

How is CHEK2-Associated Li-Fraumeni Syndrome Diagnosed?

The following tests and exams may be used to diagnose CHEK2-Associated Li-Fraumeni Syndrome:

• Complete physical exam and evaluation of family medical history
• Genetic testing
• Blood tests, as suitable
• Radiological scans, as needed
• Tissue biopsies

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the Possible Complications of CHEK2-Associated Li-Fraumeni Syndrome?

Individuals with CHEK2-Associated Li-Fraumeni Syndrome who develop cancer may experience the following complications:

• Depression
• Secondary cancers
• Malignancy of the cancer - invasion and spread of cancer to other body regions
• Increased sensitivity to radiation and external carcinogens
• Heart damage
• Surgical complications
• Lymphedema, or the swelling of an arm, can occur after surgery or radiation therapy

How is CHEK2-Associated Li-Fraumeni Syndrome Treated?

There is currently no standard treatment or cure available for CHEK2-Associated Li-Fraumeni Syndrome. In most cases, the cancers are treated similar to cancers in other patients. The treatment modalities may include surgery, chemotherapy, and radiation therapy, among others, and is based on the healthcare provider’s evaluation.

How can CHEK2-Associated Li-Fraumeni Syndrome be Prevented?

Currently, there are no available preventative measures for CHEK2-Associated Li-Fraumeni Syndrome. However, in those with an increased susceptibility to these cancers, the following measures may be considered:

• One can take certain preemptive measures to be on the lookout for the development of CHEK2-Associated LFS including, self-breast examinations, annual brain MRIs, regular colonoscopies, annual dermatology examinations, complete blood count tests, abdomen ultrasounds, etc.
• In general, it is also important to maintain a healthy lifestyle and take measures to prevent unnecessary exposure to environmental carcinogens

What is the Prognosis of CHEK2-Associated Li-Fraumeni Syndrome? (Outcomes/Resolutions)

There is currently no definitive data on the prognosis for individuals who have been diagnosed with CHEK2-Associated Li-Fraumeni Syndrome. The prognosis may vary from one individual to another.

• The prognosis may be similar to those with non-LFS associated cancers compared suitably on a stage-by-stage (and other factors) basis
• Some early research indicates that individuals with mutations in the CHEK2 gene experience decreased survival

In general, the following factors are used to determine each individual’s prognosis

• Type of cancer
• Staging of the cancer
• Location and size of the tumor
• Cell growth rate
• Likelihood of cancer returning
• Age of the individual

Additional and Relevant Useful Information for CDH1-Associated Breast Cancer:

There does not appear to be any significant difference in chemotherapy response in between individuals with and without CHEK2 gene mutations.