What is Li-Fraumeni Syndrome?
August 17, 2020
Li-Fraumeni syndrome (LFS) is a hereditary cancer syndrome that affects about 1 in every 5,000 to 20,000 people worldwide. The syndrome is named for the two physicians, Frederick Li and Joseph Fraumeni, that discovered the disorder. LFS is also more descriptively known as sarcoma, breast, leukemia and adrenal gland (SBLA) syndrome, as affected patients have a much higher than average risk of developing these cancers.
LFS is caused by adverse changes (mutations) in TP53, a gene that plays an important role in the regulation of cell growth and division. The syndrome is inherited in an autosomal dominant fashion, meaning that a child only needs to inherit one mutated copy of TP53 from an affected parent to acquire the disease. Interestingly, about 7 to 20 percent of Li-Fraumeni cases are not, in fact, hereditary, and are instead caused by new (de novo) mutations that occurred either in an unaffected parent’s reproductive cells or very early in a child’s embryonic development. Over time, additional acquired adverse mutations in other genes responsible for regulating cell growth and division accumulate in cells, which may eventually cause a normal cell to turn cancerous and divide uncontrollably. Because Li-Fraumeni patients express either a poorly functioning or nonfunctional TP53 gene product, p53, in virtually every cell of their body from birth, their odds of accumulating enough adverse mutations to convert a normal cell to a cancerous one is much higher, and often occurs at a much younger age.
To illustrate this point, individuals diagnosed with LFS have about a 50% chance of developing cancer before the age of 30 and a 90% lifetime risk of developing any type of cancer, compared to about a 40% lifetime risk in the general population of developing any type of cancer. The syndrome also increases the likelihood that an affected individual will develop more than one primary cancer in their lifetime. As mentioned previously, the syndrome is associated with the development of sarcomas, breast, brain and adrenal gland cancers, which make up about 80% of LFS cancer diagnoses. Importantly, the risk of developing invasive cancer (excluding skin cancer) is about 50% by the age of 30 (in contrast to a risk of 1% in the general population) and 90% by age 70, highlighting the importance of intensive disease surveillance in this patient population. Additionally, LFS poses a significant risk to children of affected individuals, as each child of an individual with LFS has a 50% chance of inheriting the disease.
There are several measures LFS patients can take to decrease cancer risk and assess the likelihood of syndrome inheritance in family members. Because of the heritable nature of the syndrome, physicians recommend affected patients undergo genetic counseling and genetic testing to identify a causative mutation and determine whether or not additional family members may be at risk for inheriting the disorder. Prenatal testing and preimplantation genetic testing are also options for Li-Fraumeni patients. Physicians may additionally recommend prophylactic double mastectomy in women with the syndrome, as a woman diagnosed with LFS has nearly a 100% lifetime risk of developing breast cancer in her lifetime. Li-Fraumeni patients are also advised to limit environmental exposure to carcinogens, such as UV rays, tobacco, alcohol and occupational carcinogens, and to limit diagnostic and therapeutic radiation exposure.
LFS patients must be regularly screened in order to detect cancers at the earliest possible stage. Surveillance procedures include:
- Physical examination including abdominal and pelvic ultrasound every 3-4 months from birth to 18 years of age
- Annual neurological exam from time of diagnosis
- Annual whole-body MRI (including brain) from time of diagnosis
- Physical examination including abdominal and pelvic ultrasound and dermatologic exam every 6 months from 18 years of age and older
- Annual or biannual clinical breast examination for women beginning at 20-25 years of age, annual breast MRI for women from 20-30 years of age, annual breast examination and MRI from 30-75 years of age
- Upper endoscopy and colonoscopy every 2-5 years, beginning at 25 years of age
- Periodic screening tests for hormone-producing cancers
- Regular blood tests, such as a complete blood count
Intensive surveillance plans for patients with heritable cancer syndromes, like Li-Fraumeni, provide affected patients the best chance of surviving potentially multiple cancer diagnoses. Modern hereditary cancer tests, including the Kailos Genetics’ ExpedioTM Hereditary Cancer Screening test, allow patients and their family members to identify the specific mutation responsible for their cancer syndrome, providing invaluable cancer risk information to physicians developing screening and treatment plans for affected patients. Importantly, hereditary cancer screening may identify asymptomatic individuals with an inherited cancer syndrome that can be effectively monitored and treated before a cancer has developed. Click here to learn more about ExpedioTM or contact us with any questions you may have regarding our genetic screenings.