- Author: ; Chief Editor: Max J Coppes, MD, PhD, MBA more...
Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which patients are predisposed to cancer. 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 :
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  : (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  : 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  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  or
A proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history 
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]
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. 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.
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.
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.
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.
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.
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. More than half of all tumors occur before age 30 years. 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 .
No evidence suggests either an ethnic predisposition for Li-Fraumeni syndrome or an increased or decreased frequency based on nationality.
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. 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.
Almost 90% of affected females develop breast cancer by age 60 years, with a majority occurring before age 45 years. Increased occurrence of breast cancer in males of Li-Fraumeni syndrome kindreds is not reported.
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.
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.
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