Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which patients are predisposed to cancer.[1] Li-Fraumeni syndrome is characterized by the wide variety of cancer types seen in affected individuals, a young age at onset of malignancies, and the potential for multiple primary sites of cancer during the lifetime of affected individuals. The following are the criteria for classic Li-Fraumeni syndrome, Li-Fraumeni–like syndrome, and the Chompret criteria, which provide guidelines for consideration of TP53 genetic testing.

Classic Li-Fraumeni syndrome criteria are as follows[2] :

• A proband diagnosed with a sarcoma before age 45 years and

• A first-degree relative with any cancer diagnosed before age 45 years and

• Another first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age

Li-Fraumeni–like syndrome criteria are as follows:

• Birch definition[3] : (1) a proband with any childhood cancer or sarcoma, brain tumor, or adrenocortical carcinoma diagnosed before age 45 years and (2) a first- or second-degree relative with a typical Li-Fraumeni cancer (sarcoma, breast cancer, brain tumor, adrenocortical carcinoma, or leukemia) at any age and (3) a first- or second-degree relative with any cancer before age 60 years

• Eels definition[4] : Two first- or second-degree relatives with Li-Fraumeni–related malignancies (sarcoma, breast cancer, brain tumor, leukemia, adrenocortical tumor, melanoma, prostate cancer, pancreatic cancer) at any age

Chompret criteria for Li-Fraumeni syndrome are as follows:

• A proband who has (1) a tumor belonging to the Li-Fraumeni tumor spectrum (soft-tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, or bronchoalveolar lung cancer) before age 46 years and (2) at least one first- or second-degree relative with a Li-Fraumeni tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors[5] or

• A proband with multiple tumors (except multiple breast tumors), 2 of which belong to the Li-Fraumeni tumor spectrum and the first of which occurred before age 46 years[6] or

• A proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history[7]

While most hereditary family cancer syndromes involve 1 or 2 specific tumor types, members of Li-Fraumeni syndrome kindreds are at risk for a wide range of malignancies, with particularly high occurrences of breast cancer, brain tumors, acute leukemia, soft-tissue sarcomas, bone sarcomas, and adrenal cortical carcinoma. Several other cancers have been seen at lower rates in Li-Fraumeni syndrome kindreds, including cancers of the lung, colorectum, stomach, prostate, ovary, and pancreas, as well as lymphoma, melanoma, and choroid plexus carcinoma.[8, 9]

Although osteosarcoma and chondrosarcomas occur frequently, no evidence suggests increased occurrence of Ewing sarcoma in association with Li-Fraumeni syndrome.

Li-Fraumeni syndrome has been linked to germline mutations of the tumor suppressor gene TP53. Mutations can be inherited or can arise de novo early in embryogenesis or in one of the parent's germ cells.[10] Approximately 70% of Li-Fraumeni syndrome kindreds and 40% of Li-Fraumeni–like families have germline mutations in the TP53 tumor suppressor gene.[11, 3] Over 767 germline mutations and 29, 881 somatic mutations have been identified in the TP53 gene.[1]

TP53, which is located on band 17p13.1, codes for a 53-kd nuclear protein transcription factor that has important regulatory control over cell proliferation and homeostasis, specifically the cell cycle, DNA repair processes, and apoptosis.

Somatic (nongermline) TP53 tumor suppressor gene mutations are common in sporadic human cancers, suggesting that TP53 alterations play an important role in the development of cancer. Moreover, a broad range of cell line and transgenic animal experiments show direct involvement of TP53 mutations in malignant transformation. Alterations of p53 function are the result of either loss of function of wild type p53, increased or aberrant protein function, or dominant negative effects of the mutated protein.

This impairment in p53 function is thought to lead to loss of protection against the accumulation of genetic alterations. p53 and the ubiquitin ligase HDM2 have been shown to interact with another E3 and E4 ubiquitin ligase UBE4B to induce the polyubiquitination and degradation of p53, which prevented apoptosis of medulloblastoma and ependymoma cells. Overexpression of UBE4B was also associated with amplification of its gene in brain tumors.[12]

These laboratory data support the hypothesis of constitutional mutations as the etiology of Li-Fraumeni syndrome. Although inactivation of TP53 confers a predisposition to cancer, this alone is not sufficient because not all families with classic Li-Fraumeni syndrome or Li-Fraumeni–like syndrome have detectable alterations of TP53. The absence of detectable germline TP53 mutations in some families suggests that other genes might be involved in the syndrome or that the p53 protein may undergo posttranslational alterations.

Specifics of the inherited TP53 mutation may have a significant effect on the cancer phenotype in the affected family. Most Li-Fraumeni syndrome–associated TP53 defects involve missense point mutations occurring in a hot-spot region of exons 5-8, a portion of the gene that codes for the core DNA-binding domain of the protein. Missense mutations lead to a stable but inactive protein, which accumulates in the nucleus of tumor cells. Frameshift, nonsense, and splice-site mutations can also be present, but do not lead to accumulation of p53 protein.

Kindreds with constitutional mutations in the hot spot region display more aggressive cancer phenotypes than patients with other TP53 mutations and those patients that appear to lack any heritable defect. Families with mutations in the hot spot region include those with younger probands at the time of cancer diagnosis. Mutations in exons 5-8 are also associated with a higher overall incidence in family members with breast cancer and CNS tumors diagnosed when patients are younger than 45 years, suggesting a higher rate of penetrance of the cancer phenotype in families with these types of inherited TP53 defects.

Single nucleotide polymorphisms in both TP53 and MDM2, an integral component of p53 function, appear to influence the age of cancer onset in Li-Fraumeni syndrome.[13, 14] Short telomeres are also associated with younger age of onset of first cancer in Li-Fraumeni syndrome families.[15, 16] Genomic copy number variation, used as a marker of genetic instability, is higher in patients with germline TP53 mutations than in healthy controls.[17]

 

Frequency

United States

Li-Fraumeni syndrome appears to be rare, with approximately 400 reported families described in the literature since it was first characterized in 1969; its actual population incidence is unknown. Each year, approximately 5-10 cases of soft-tissue sarcoma occur per 1 million children younger than 15 years. In a study of sarcoma patients, 10% of families with either an osteosarcoma diagnosed before age 20 years or a soft-tissue sarcoma diagnosed before age 16 years were found to have germline TP53 mutations.[18]

A study by Yurgelun et al examined the frequency of germline TP53 alterations in patients with early-onset colorectal cancer. The study found that out of the 457 eligible participants, 6 (1.3%) carried germline missense TP53 alterations, however, none of these TP53 alterations met the clinical criteria for Li-Fraumeni syndrome.[19]

Mortality/Morbidity

The cancers that occur most commonly in members of Li-Fraumeni syndrome kindreds are breast cancer, brain tumors, acute leukemia, soft-tissue sarcomas, osteosarcoma, and adrenal cortical carcinoma. Individuals with Li-Fraumeni syndrome have a lifetime cancer risk that approaches 100% by age 70 years.[20] More than half of all tumors occur before age 30 years.[21] Patients with Li-Fraumeni syndrome can be successfully treated for the initial cancer, however, radiation therapy is avoided, when possible, due to several case reports and preclinical evidence demonstrating an increased risk in radiation-induced cancers in these patients.[22, 23]  Furthermore, Li-Fraumeni patients are at significant risk for the development of a second primary malignancy[24] .  

Race

No evidence suggests either an ethnic predisposition for Li-Fraumeni syndrome or an increased or decreased frequency based on nationality.

Sex

Li-Fraumeni syndrome has an autosomal dominant inheritance pattern; therefore, the genetic predisposition for cancer equally affects males and females. Cancer penetrance is 93% for female carriers compared with 73% for male carriers, owing to the increased risk of breast cancer in females.[20] It is estimated that 5-8% of women diagnosed with early-onset breast cancer (at < 30 y) with a negative family history may have a mutation in the TP53 gene.[25]

Almost 90% of affected females develop breast cancer by age 60 years, with a majority occurring before age 45 years.[26] Increased occurrence of breast cancer in males of Li-Fraumeni syndrome kindreds is not reported.

Age

Although approximately 10% of cancers occur in individuals younger than 45 years in the general population, more than half of the cancers occur in Li-Fraumeni syndrome family members younger than 45 years.

The risk for developing soft-tissue sarcomas is greatest before age 10 years. Brain cancer also appears early in childhood, with a second peak in the fourth to fifth decade of life. Osteosarcoma risk peaks during adolescence. Breast cancer risk for females with Li-Fraumeni syndrome increases significantly at around age 20 years and continues to increase in adulthood.[20]

Bougeard et al updated the clinical presentation of 1,730 French patients suggestive of LFS by identifying 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations. The study found that in children, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS). In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients.[27]

Patients should be counseled about the signs and symptoms of cancer.  They should be encouraged to report any unusual findings, as these may relate to a cancer presentation.

Because of the significantly increased risk of cancer associated with Li-Fraumeni syndrome (LFS), obtaining a thorough family cancer history over at least 3 generations is very important. The history should screen for all tumor types, with particular attention to soft-tissue sarcomas, osteosarcoma, brain tumors, leukemia, and adrenal cortical carcinoma. Occasionally, family history only becomes positive after several years; therefore, updating the family cancer history in patients with Li-Fraumeni syndrome is important.

Obtaining a thorough family history with particular emphasis on cancer can be tedious, but it is an important part of the evaluation of every child diagnosed with a malignancy.

Early age of onset, positive family history, and multiple primary malignancies suggest a hereditary cancer syndrome.

Birch and colleagues found that the probands in families with significant cancer history are more likely to be males younger than 24 months at time of diagnosis and are more likely to have tumors with embryonic histologic findings when compared with other children (not affected by Li-Fraumeni syndrome) diagnosed with soft-tissue sarcomas.[28]

Birch et al also showed that mothers of children with soft-tissue sarcomas and osteosarcomas have a 3-fold increased risk of developing breast cancer at young ages.[29]

Curtin et al used the Utah Population Database to look at first-, second-, and third-degree family members of 4,482 pediatric subjects with cancer diagnosed before age 19 years over a 43-year period, compared with matched population controls. They showed that first-degree siblings of pediatric cancer cases faced a 2-fold increased risk of a pediatric cancer diagnosis, with the risk increasing to 3.6-fold if the child was diagnosed prior to age 5 years. Although first-degree relatives of pediatric cases have a slightly increased risk of adult tumors, when they do develop cancer they have a 1.7-fold risk of developing a tumor in the Li-Fraumeni spectrum.[30]

 

No specific physical findings are attributed to individuals affected by Li-Fraumeni syndrome other than the findings related to the presentation of specific cancers.

Physical findings related to specific cancers:

• Breast lump (breast cancer)

• Neurologic changes including seizures, headaches, vomiting, and gait abnormalities (brain cancers)

• Formation of a soft-tissue mass (soft-tissue sarcoma) or a bone-related mass (bone sarcoma)

• Fevers, pancytopenia, fatigue, pallor, bruising, bleeding, bone pain (acute leukemia)

• Signs of virilization including prepubertal genital hair, clitoromegaly or increased penile size, deep voice, and acne associated with an abdominal mass (adrenal cortical carcinoma)

Annual physical examination as part of well care should be performed, including detailed skin and neurological assessments.[31]

Breast self-examination training and regular monthly breast self-examination, starting at age 18 years.[31]

Clinical breast examination should be performed every 6-12 months, starting at age 20-25 years.[31]

In patients with an identified TP53 mutation, when a tumor may arise is unknown; thus, having a physician with whom one has an established relationship may assist in noting changes in the physical examination.

Inheritance of a germline mutation of the TP53 tumor suppressor gene is a predisposing genetic factor in Li-Fraumeni syndrome family members.  It is inherited in an autosomal dominant fashion

Evaluation for constitutional TP53 mutation in patients with cancer and a family history or presentation suggestive of potential Li-Fraumeni syndrome (LFS) is warranted to aid in predicting future risk of other primary malignancies for the patient as well as for other family members.

Some authors have advocated for genetic screening in children who are diagnosed with specific cancers, irrespective of family history, including adrenocortical carcinoma and choroid plexus carcinoma at any age, rhabdomyosarcoma before age 3 years, and possibly osteosarcoma before age 10 years, as several groups have documented a 50-100% rate of germline TP53 mutations in these subsets.[9, 6, 32]

Although most reported Li-Fraumeni syndrome–related TP53 mutations occur in exons 5-8, optimal DNA analysis should include evaluation of the entire coding and noncoding portions of the gene (exons 1-11) by automated sequencing methods. Because TP53 mutations are constitutional (ie, germline), DNA derived from any clinical source can potentially be evaluated. Peripheral blood leukocytes are the most easily obtained source and are typically collected in citrate or heparin anticoagulant tubes.

Considerations should be made regarding the use of testing for germline TP53 mutations. The National Comprehensive Cancer Network (NCCN) Guidelines Testing Criteria should be used as a guide. Patients and families with histories consistent with Li-Fraumeni syndrome or with presentations of cancer suggestive of a possible germline TP53 mutation should be counseled regarding genetic testing.

Initially, testing should be limited to an affected individual (ie, in whom cancer has been diagnosed) to determine if a TP53 mutation is present. Then, subsequent testing of at-risk family members can be limited to the specific mutation previously documented.

Prior to testing, ensure that the significance of either a positive or a negative result is clear to all patients and relatives. Explain that no simple screening or intervention exists that can eliminate the potential of developing cancer for those who carry the mutation.

Family members whose test results are negative for the TP53 mutation but for whom the mutation was previously established in an affected relative can be reasonably reassured of a low risk of developing cancer at an early age. However, they should understand that this does not mean they are immune to developing a malignancy at some point. Generally, cancer is a multifactorial condition, and the risk may depend on health-related behaviors (eg, smoking, environmental exposures, diet) and other potential genetic factors.

Breast cancer screening

Annual breast MRI screening (preferred) or mammogram (if MRI is unavailable), at age 20-29 years.[31]

Annual mammogram and breast MRI screening, at age 30-75 years.[31]

Consider management on an individual basis after age 75 years.[31]

Colorectal cancer screening

Colonoscopy should be performed every 2-5 years starting no later than age 25 years.[31]

Use of other imaging modalities

The utility of whole body MRI, as a screening tool, is being investigated in several international trials.[31]

Example of a surveillance program[32]

A clinical surveillance protocol (Toronto protocol) for TP53 mutation carriers was implemented at the Hospital for Sick Children in Toronto in 2004. The protocol includes frequent laboratory and radiographic screening for adrenocortical carcinoma, brain tumors, soft-tissue and bone sarcoma, leukemia/lymphoma, breast cancer, and colon cancer.

The study included 33 TP53 mutation carriers from 8 families; 18 self-elected to be in the surveillance group, and 15 self-elected to not have surveillance. Of the 18 patients in the surveillance group, 10 asymptomatic tumors were detected in 7 patients. Five tumors were malignant and 5 were low-grade or premalignant. All 7 patients were alive at the end of 24-month follow-up. Of the 16 patients in the nonsurveillance group, 12 symptomatic, high-grade, high-stage tumors were found in 10 patients. Only 2 of the 10 patients were alive at the end of follow-up.

Three-year overall survival was 100% in the surveillance group and 21% in the nonsurveillance group (P = .0155).

Among those diagnosed with a cancer, survival was better in the surveillance group than in the nonsurveillance group (100% vs 20%, respectively; P = .0417).

No clear evidence suggests that individuals with Li-Fraumeni syndrome (LFS) diagnosed with cancers should be treated differently from other patients with cancer through the modalities of chemotherapy or surgery. Radiation therapy should be used with caution owing to concerns about increased risk for radiation-induced second primary tumors in Li-Fraumeni syndrome patients. Specifics of therapy are related to the type of cancer.

Based on expert opinions and limited evidence, the National Comprehensive Cancer Network (NCCN) has provided an algorithm for the testing and management of Li-Fraumeni syndrome in adults.

Physicians should discuss risk-reducing, prophylactic mastectomy with Li-Fraumeni syndrome women. It should be considered on a case-by-case basis depending on the degree of cancer risk and reconstructive options available.

Genetic counseling for families with Li-Fraumeni syndrome should be provided to ensure appropriate understanding of potential risk and possible evaluation of genetic predisposition markers.

In addition, Li-Fraumeni syndrome patients can develop high levels of anxiety, depression, and clinically relevant distress. Psychological monitoring is important, and appropriate support should be provided.

Improvements in the treatment of childhood cancers, including acute lymphocytic leukemia, soft-tissue sarcomas, and osteosarcomas, have led to long-term survival in most children diagnosed with these cancers. Potential late effects for the survivors include second primary malignancies. These may occur, in part, because of the carcinogenic effects of chemotherapy and radiation therapy; however, they may also be due to genetic predispositions such as constitutional TP53 mutations.

Clinical evaluation of family members who are potentially affected by Li-Fraumeni syndrome (LFS) should be considered. Although some sources have recommended frequent laboratory and radiographic monitoring of children in Li-Fraumeni syndrome kindreds, no evidence has been established that screening tests significantly improve survival rates in other nonaffected family members.

Factors that complicate the counseling of patients regarding tumor risk and preventative measures include the wide variety of cancer types that can occur, the lifetime cancer risk, and an incomplete understanding of the variability of penetrance.

Prediction of cancer risk is feasible via carrier testing in Li-Fraumeni syndrome kindreds in whom specific constitutional TP53 mutations are documented.

A major issue in Li-Fraumeni syndrome is whether to test children, especially when the child has not been affected. Whether testing should be done, whether the child should be informed of the results, how to talk to children about inherited predisposition to cancer, and what surveillance should be implemented are areas of concern. The medical and psychological risks and benefits to the child need to be carefully considered.[20]

Known affected individuals, either because of a history of a previous cancer consistent with Li-Fraumeni syndrome or because they carry a TP53 mutation, should be advised regarding the following:

• The potential risk of the wide variety of related cancers and the screening necessary

• The importance of having an established physician or other healthcare professional who is cognizant of the syndrome involved in ongoing care

• The potential for genetic testing to evaluate potential risk for family members

Individuals who are at risk based on Li-Fraumeni syndrome family history but who have not had cancer and for whom no TP53 mutation information is available should be closely monitored and offered TP53 testing.

Prophylactic mastectomy decreases the risk of breast cancer in women with Li-Fraumeni syndrome, but it does not decrease the risk for other malignancies. See Imaging Studies for other surveillance methods and strategies.

Children in families with Li-Fraumeni syndrome who survive an initial cancer have a relative risk of developing a second cancer that is 83 times greater than that of the general population. The risk for a second cancer increases with younger age at diagnosis of the first cancer.

A second cancer generally occurs 6-12 years after the first cancer. The cumulative probability of a person affected by Li-Fraumeni syndrome developing a second cancer is 57% at 30 years after developing the first cancer.[8]

The risk for a second cancer increases with radiation exposure. Patients with Li-Fraumeni syndrome have a predilection for developing subsequent primary tumors (especially sarcomas) in prior radiation fields.

A study by Teepen et al evaluated individual chemotherapeutic agents and solid cancer risk in childhood cancer survivors and reported that compared to other cancers, the doxorubicin-breast cancer dose response was stronger in survivors of Li-Fraumeni syndrome-associated childhood cancers.[38]

Genetic counseling for at-risk individuals in families with Li-Fraumeni syndrome is important to provide the necessary information to allow decision making regarding TP53 testing, if it is feasible, and to discuss the need for close medical follow-up care.

Individuals affected by Li-Fraumeni syndrome who are successfully treated for cancer must understand the significant risk of developing further primary malignancies and the need for close medical follow-up care.