Continuing Education Activity

Li Fraumeni syndrome, also known as sarcoma, breast, leukemia, and adrenal gland (SBLA) syndrome, is a rare inherited autosomal dominant disorder associated with abnormalities in TP53, a tumor suppressor protein gene. This activity illustrates the evaluation and management of Li Fraumeni syndrome and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Describe the role of TP53 in the etiology of Li Fraumeni syndrome.
• Explain the pathophysiology of Li Fraumeni syndrome.
• Summarize the Chompret criteria in the evaluation of Li Fraumeni syndrome.
• Review the importance of improving care coordination among the interprofessional team members to provide genetic counseling, medical care, and support services for patients affected by Li Fraumeni syndrome.

Introduction

In 1969, a remarkable cancer predisposition syndrome was reported by Li and Fraumeni.[1] Li-Fraumeni syndrome (LFS) is an inherited autosomal dominant disorder that is usually associated with abnormalities in the tumor suppressor protein P53 gene (TP53) located on chromosome 17p13.[2] It is also known as the sarcoma, breast, leukemia, and adrenal gland (SBLA) cancer syndrome. LFS variants include LFS1, LFS2, LFSL. LFS1 is associated with mutations in TP53, a tumor suppressor gene. LFS2 is associated with mutations in CHEK2 (checkpoint kinase two), also a tumor suppressor gene. LFS-L are individuals that do not have detectable mutations in P53.

Etiology

There are three genes identified with Li-Fraumeni syndrome (LFS) Tp53 17p13, 1q23, and checkpoint kinase two genes CHEK2 locus at 22q12.1.[2] In these three genes, TP53 mutations are most common. P53 has many mechanisms of anticancer function; it plays a role in apoptosis, maintaining genomic stability, and inhibits angiogenesis. When DNA has sustained damage, it plays a role in the activation of DNA repair proteins. It can stop cell growth at the G1/S regulation point, which gives time for DNA repair proteins to fix the damage. If the damage is irreversible, it can trigger apoptosis. Checkpoint kinase 2 (Chek2) regulates the activities of P53.[3][4]

In TP53 mutations, one mutant allele is generally inherited by individuals with Li-Fraumeni syndrome; the other allele is deleted or somatically mutated, which leads to loss of functional P53 protein. Missense mutations are the most common to occur, usually in exons 5 to 8 which is the DNA binding region of the gene. When mutation testing is done targeting exons 5-8 (these are the usual targets for testing), nearly 70% of Li–Fraumeni families meeting the required diagnostic criteria harbor P53 mutations. Partial loss of alleles presents with less family history, decreased numbers of tumors, and late disease onset.[5]

Not all individuals with Li-Fraumeni syndrome have TP53 mutations. It also can be due to an alteration in gene promoter which causes defective protein expression. It may also be due to new mutations that have not been described.

Epidemiology

Li-Fraumeni (LFS) is a rare syndrome, as over 500 families with LFS have been reported in the literature. There are likely over 1,000 multigenerational families worldwide with LFS. Children with a diagnosis of adrenocortical carcinoma have the highest occurrence of P53 mutations. The syndrome is also associated with childhood brain tumors, osteosarcomas, and rhabdomyosarcomas. Patients with multiple primary tumors have a high incidence of P53 mutations.[6][7]

Mutations in the core binding protein of TP53 have an increased risk of cancer. TP53 mutations have a high penetrance. The lifetime risk for women is 90 percent by age 60 years while in men the estimated lifetime risk is about 73 percent.[8] While most hereditary family cancer syndromes involve specific tumor types, members of LFS are at risk for a wide range of malignancies, with particular occurrences of breast cancer, bone sarcomas, and soft tissue sarcomas. Several other cancers have been reported but at a lower incidence in Li-Fraumeni syndrome.[9]

The risk of developing multiple primary cancers is high in members of families with Li-Fraumeni syndrome compared to the general population. This excess risk mainly involves cancers characteristic of LFS, this risk is further increased in survivors of childhood cancers, and these patients require close monitoring for early cancer signs.[10]

Patients with LFS are successfully treated during the initial cancer occurrence. However, radiation therapy should be avoided, when possible, due to several case reports and preclinical evidence showing an increased risk of radiation-induced cancers in these patients.[11] Li-Fraumeni patients are at a high risk of developing a second primary malignancy.[12]

Pathophysiology

Li-Fraumeni syndrome (LFS) occurs due to germ-line mutations in TP53. TP53 is a tumor suppressor gene, which is located on band 17p13.1, which codes for a 53-kD nuclear protein transcription factor that has important regulatory control over cell proliferation and homeostasis, specifically apoptosis, DNA repair, and cell cycle. Mutations can arise in one of the parent's germ cells, de novo during embryogenesis, or can be inherited. Changes in P53 function results from either increased or aberrant protein function or loss of function of wild-type P53. Most Li-Fraumeni syndrome TP53 mutations occur as missense point mutations in a hot-spot region of exons 5-8.[13] This is the gene portion that codes for the core DNA-binding domain of the protein. This kind of mutation leads to stable but inactive protein, which accumulates in the nucleus of tumor cells. Any mutation like frameshift, nonsense and splice-site can also be present but do not lead to the accumulation of p53 protein.

The cell loses protection against genetic alterations when P53 mutations occur. Ubiquitin ligase HDM2 and P53 interact with E3 and E4 proteins, which induce polyubiquitination and degradation of P53, which prevents apoptosis.[14][15] They are also associated with the overexpression of UBE4B and with the amplification of these genes in brain tumors. The absence of P53 mutations in some families indicates that P53 protein may undergo posttranslational modifications, or other genes may be involved. Genetic copy number variation, used as an indicator of genetic instability, are higher in patients with germline TP53 mutations than in healthy individuals.

Mutations Associated with Younger Age of Onset in Li-Fraumeni Syndrome

• Short telomeres
• Genetic modifiers, including the MDM2-SNP309 polymorphism, and genetic anticipation
• P53-related cancers, usually breast cancer, soft tissue sarcoma, osteosarcoma (bone cancer), leukemia, brain tumors, adrenocortical carcinoma (cancer of the adrenal glands), and other cancers[16][17][18]

History and Physical

The family history of cancer, young age at initial diagnosis, and multiple malignancies suggest cancer syndromes that are hereditary. Patients should be informed adequately about all the signs and symptoms of cancer. They must be counseled to consult whenever they have any unusual signs or symptoms related to cancer. A complete family history of multiple generations is very important due to a significant increase in cancer risk within families.[19] The history should include screening for multiple tumor types especially sarcomas, breast, leukemia, and adrenocortical tumors.[20] Sometimes risk becomes evident only after several years, so it is very important to update the family history regularly. Obtaining a thorough family history can be difficult, but it is an important part of evaluating every child diagnosed with an early malignancy. History should emphasize all cancers in the Li-Fraumeni syndrome spectrum.[21]

No specific physical findings are seen in individuals affected by Li-Fraumeni syndrome that differ from the findings related to specific cancers. Physical findings to watch for in specific cancers include:

• Neurologic features like seizures, vomiting, headaches, and gait changes related to brain cancers
• A breast lump in breast cancer
• Soft-tissue mass or a bone-related mass in soft tissue sarcoma or bone sarcoma
• Pancytopenia, fatigue, fever, weight loss, loss of appetite, swollen lymph nodes, bleeding gums, and infections in acute leukemia
• Virilization including prepubertal genital hair, increased penile size, clitoromegaly, deep voice associated with an abdominal mass in adrenal cortical carcinoma[19][22]

An annual physical examination should be performed, including breast, skin, and neurological assessments.

Evaluation

Initially, the diagnosis of Li-Fraumeni was done using clinical criteria based on signs and symptoms the patient and family have. With advanced genetic testing, patients can now know if they carry a copy of the TP53 tumor mutation before showing any signs of LFS. Genetic testing for TP53 mutations is very important. It is important to offer genetic counseling and testing to all relatives at risk of having a familial TP53 pathogenic variant. Genetic testing only detects approximately 70% to 75% of cases. Genetic counseling must be done to consider genetic testing, and if it concludes that a patient is carrying a copy of TP53 mutations, the patient must be counseled about surveillance and continuously screened for LFS related types of cancer.[23]

The decision to do genetic counseling and TP53 mutation testing should be considered for the following patients:

Diagnostic Criteria

Classic Li-Fraumeni syndrome -  It is diagnosed when the person has all the following criteria:[24]

• A sarcoma diagnosed before age 45.
• A first-degree relative, parent, sibling, or child with any cancer before age 45.
• Any cancer before age 45 or a sarcoma at any age in first-degree or second-degree relative (grandparent, aunt/uncle, niece/nephew, or grandchild).

Chompret Criteria[25]

This includes brain tumor, adrenocortical cancer, breast cancer in the proband, and also has a lower age cutoff of <31 years. Consider a diagnosis of LFS for anyone with a personal and family history that meets one of the following three criteria.

• A tumor belonging to the LFS spectrum before the age of 46. This includes any of these diseases: premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, adrenal cortical tumor, brain tumor, leukemia, lung cancer.AND
• At least one first- or second-degree relative with an LFS tumor before age 56 years or multiple tumors, except for breast cancer if the proband has breast cancer.
• A person with multiple tumors, except when two belong to the LFS tumor spectrum with the first occurring before age 46.
• A person who is diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history.

Li-Fraumeni-like syndrome (LFL) is another term for families who do not meet the set classic criteria.

LFL-1, Birch Definition[26]

• A person diagnosed with any brain tumor, adrenocortical tumor, sarcoma, breast cancer before age 45AND
• A typical LFS cancer in a first or second-degree relative at any age.AND
• A first-degree or second-degree relative with any cancer before age 60.

LFL-2, ELES Criteria[26]

Two relatives (first-degree or second-degree) diagnosed with a typical LFS cancer at any age.

• Individuals who have either classical criteria for LFS or the Chompret criteria or who have other combinations of cancer and family history that put them at risk for LFS or LFL syndrome, but in whom there is no known mutation in the family. Negative test results do not rule out LFS and these patients should be managed as if they have LFS.
• Women with early-onset breast cancer (less than 31 years) and without a detectable breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutation. It increases the index of suspicion for Li-Fraumeni syndrome if there is a family history of sarcoma, brain tumor, or adrenocortical carcinoma. A negative result in these individuals does not rule out LFS.[27]
• Patients with a family history of known TP53 mutation to test for the known mutation. A negative test in these individuals rules out LFS. Those who choose not to undergo testing should be managed as if they harbor the TP53 mutation, at least until 50 years of age.

Individuals with some cancers irrespective of age or family history should undergo genetic testing for TP53 deleterious gene mutations. These include a) adrenocortical carcinoma b) choroid plexus carcinoma at any age c) rhabdomyosarcoma before age three years d) osteosarcoma before age ten years e) childhood sarcoma (except Ewing sarcoma).[28]

•  Consider prenatal testing for at-risk pregnancies in situations where a specific TP53 mutation has been identified. 

Cancer Surveillance

Cancer surveillance is required for individuals who are at risk based on the history of LFS malignancy, the patient with known TP53 tumor mutation, or those with increased risk in a family with LFS but without an identifiable mutation or who have not undergone mutation testing.[12][29][30]

• Complete annual physical examination and medical evaluation for unexplained symptoms
• Whole-body magnetic resonance imaging (WBMRI) annually
• Abdominal and pelvic ultrasound (US) every 3 to 4 months in children and annually in the adult
• Biochemical markers for adrenocortical functions
• Blood tests every 4 months (complete blood count, lactate dehydrogenase, and erythrocyte sedimentation rate)
• Breast cancer monitoring - breast self-examination monthly, biannual clinical breast examination with a healthcare provider, and annual breast imaging beginning at age 20 to 25 years (preferably MRI breast due to radiation exposure from mammography)
• Colonoscopy every 2 to 5 years, beginning at age 25 to 30 or 5 years before the earliest known colon cancer in the family
• Blood test for biochemical markers and brain MRI as per Toronto protocol

Treatment / Management

There is currently no procedure or treatment option to repair mutations in the P53 gene as P53 is not a drug target yet. In general, radiation therapy should be avoided in patients with Li-Fraumeni syndrome as individuals are at high risk of radiation-induced secondary cancers. Similarly, exposure to computed tomography (CT) scans or X-rays should be avoided.[31] Li-Fraumeni syndrome is a complex syndrome with many implications for individuals and their families, so it is suggested patients with LFS or suspected LFS consult with a physician or health care system that has experience in treating patients with Li-Fraumeni syndrome and providing medical care, genetic counseling, and special support services.[19][32]

No evidence suggests that individuals with LFS diagnosed with cancers should be treated uniquely from other patients with the same cancer. However, in breast cancer, complete mastectomy rather than lumpectomy which is usually followed by radiation therapy is generally preferred because of the risks of second breast cancers or radiation-induced neoplasms.[33][34] Physicians should discuss the need for risk-reducing mastectomy; it must be considered case-by-case, depending on the degree of cancer risk and reconstructive options.

Li-Fraumeni syndrome patients are prone to anxiety, depression, and clinically relevant distress. Psychological monitoring is recommended and providing support is very important.

Differential Diagnosis

• Hereditary breast and ovarian cancer syndrome (HBOC)
• Lynch syndrome
• Multiple endocrine neoplasia[35]

Prognosis

There is no difference in the treatment of cancers in LFS and other cancers that occur sporadically. Advancement in the treatment of childhood cancers has increased the long-term survival for most children. Usual complications in survivors include second primary malignancies, which mostly occur within 6 to 12 years after the first cancer.[36][37]

A second cancer may occur due to genetic predispositions such as constitutional TP53 mutations. The risk for a second cancer increases with younger age at diagnosis of first cancer. Second cancer risk increases with radiation exposure, so these individuals should avoid or minimize exposure to diagnostic and therapeutic radiation when possible. They have a predilection for developing subsequent primary tumors (especially sarcomas) in prior radiation fields.[7][38]

The cumulative probability of a person affected by LFS developing a second cancer is close to 60% at 30 years after developing the first cancer.

Complications

Individuals with Li-Fraumeni syndrome can become resistant to chemotherapy. The risk of other primary cancers is increased if a germline mutation has occurred. There is evidence that a TP53 genetic mutation can cause a patient to have an increased sensitivity to ionizing radiation. Individuals with germline TP53 mutations should avoid or minimize exposure to diagnostic and therapeutic radiation when possible.[39]

Consultations

Referral to a genetic counselor is recommended to obtain a detailed family history, genetic counseling, discuss risks of cancer, and plan for cancer screening.[40][41][42]

Deterrence and Patient Education

Parents and patients should be informed adequately about all the signs and symptoms of cancer. They must be counseled to seek care whenever they have any unusual signs or symptoms that may be related to a cancer. Patients should be trained to perform a breast self-examination regularly every month, starting at age 18 years. Psychological monitoring is very important as these patients can develop anxiety or depression.

Enhancing Healthcare Team Outcomes

The management of patients with Li-Fraumeni syndrome is best accomplished with an interprofessional team approach involving a geneticist, internist, oncologist, psychiatrist, and radiologist. Li-Fraumeni syndrome patients are prone to anxiety, depression, and clinically relevant distress. Psychological monitoring by an interprofessional team of oncology specialty nurses and oncologists is important and providing support is very important for good outcomes. [Level 5]