Practice Essentials
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which mutations in the TP53 gene result in elevated predisposition to cancer. [1] Affected individuals present with a wide variety of high-risk cancers, often at a young age, and may have multiple primary cancers during their lifetime. [2, 3]
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 [4] :
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A proband diagnosed with a sarcoma before age 45 years and
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A first-degree relative with any cancer diagnosed before age 45 years and
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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 is a cancer predisposition disorder in individuals who do not meet all the criteria for classic Li-Fraumeni syndrome; two definitions have been developed, as follows:
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Birch definition [5] – (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
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Eeles definition [6] – 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:
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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 [7] or
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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 [8] or
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A proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history [9]
Although 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. The "core" cancers occur at particularly high frequencies and include soft-tissue sarcomas, osteosarcoma, pre-menopausal female breast cancer, brain tumors, 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 leukemia, lymphoma, and melanoma. [10, 11]
A germline mutation of the TP53 tumor suppressor gene results in Li-Fraumeni syndrome. A range of mutations, including both missense and truncation, of TP53 have been found. The mutation may be inherited or occur de novo..
Pathophysiology
Li-Fraumeni syndrome has been linked to pathogenic germline mutations of the tumor suppressor gene TP53. 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 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 DNA damage, increased survival and proliferation, and malignant transformation. Individuals with Li-Fraumeni syndrome have a constitutional abnormality in one copy of the TP53 gene, and tumors from these patients have a second acquired mutation or deletion, resulting in complete loss of function of the TP53 gene.
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 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 of 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. [12, 13]
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. [14, 15] Short telomeres are also associated with younger age of onset of first cancer in Li-Fraumeni syndrome families. [16, 17] Genomic copy number variation, used as a marker of genetic instability, is higher in patients with germline TP53 mutations than in healthy controls. [18]
Although inactivation of TP53 confers a predisposition to cancer, 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 there may be variants in TP53 that have yet to be discovered, that the p53 protein may undergo post-translational alterations that contribute to tumorigenesis, or that other genes might be involved in the syndrome.
Epidemiology
United States statistics
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. [19]
A study by Yurgelun et al in patients with early-onset colorectal cancer found that 6 of the 457 eligible participants (1.3%) carried germline missense TP53 alterations. However, none met the clinical criteria for Li-Fraumeni syndrome. [20]
Race-, sex-, and age-related demographics
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 nearly 100% for female carriers compared with 73% for male carriers, owing to the increased risk of breast cancer in females. Almost 90% of affected females develop breast cancer by age 60 years, with a majority occurring before age 45 years. [21] Increased occurrence of breast cancer in males of Li-Fraumeni syndrome kindreds is not reported. It is estimated that 5-8% of women diagnosed with early-onset breast cancer (at < 30 years) with a negative family history may have a mutation in the TP53 gene. [22]
Age
In Li-Fraumeni syndrome families, more than half of the cancers occur in family members younger than 45 years; this compares with approximately 10% of cancers in the general population.
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. [23]
A review by Bougeard et al of 415 mutation carriers in 214 French families harboring 133 distinct TP53 alterations found that in children, the Li-Fraumeni syndrome tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS). In adults, the tumor distribution was characterized by breast cancer, seen in 79% of the females, and STS in 27% of the patients. The mean age of cancer onset varied with the mutation type: 21.3 in carriers harboring dominant-negative missense mutations, 28.5 years in those with loss-of-function mutations, and 35.8 years in those with genomic rearrangements. [24]
Prognosis
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 but can also occur concurrently, during active management of 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. [10]
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. [25]
Morbidity/mortality
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. [23] More than half of all tumors occur before age 30 years. [26] 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 of radiation-induced cancers in these patients. [27, 28] Furthermore, patients with Li-Fraumeni syndrome are at significant risk for the development of a second primary malignancy [29] .
Patient Education
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.
Tables
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