eMedicine Specialties > Pediatrics: General Medicine > Oncology

Li-Fraumeni Syndrome

Author: Kavita Patel, MD, Clinical Postdoctoral Fellow in Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine
Coauthor(s): Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA; Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories
Contributor Information and Disclosures

Updated: Dec 1, 2008

Introduction

Background

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 3 criteria must be met for a diagnosis of Li-Fraumeni syndrome:

1. A proband diagnosed with sarcoma when younger than 45 years
2. A first-degree relative with any cancer diagnosed when younger than 45 years
3. Another first-degree or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age

Most hereditary family cancer syndromes involve 1 or 2 specific tumor types, whereas 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. Although osteosarcoma and chondrosarcomas occur frequently, no evidence suggests increased occurrence of Ewing sarcoma in association with Li-Fraumeni syndrome. Since Li-Fraumeni syndrome was first characterized in 1969, more than 100 Li-Fraumeni syndrome kindreds have been described.

Pathophysiology

Li-Fraumeni syndrome has been linked to germline mutations of the tumor suppressor gene p53 (TP53). Mutations can be inherited or can arise de novo early in embryogenesis or in one of the parent's germ cells.¹ Subsequent studies analyzing the coding and noncoding portions of TP53 have shown that approximately 70% of Li-Fraumeni syndrome kindreds have constitutional (germline) mutations of 1 of the 2 copies of the TP53 tumor suppressor gene; the second copy is normal.² TP53, which is located on chromosome band 17p13, 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.

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 have detectable alterations of TP53. This could be a result of how TP53 alterations are assessed. Previous analyses only measured certain portions of the gene. In addition, the p53 protein may undergo posttranslational alterations. Finally, Li-Fraumeni syndrome can result from defects in other genes that participate in the cell cycle regulatory pathway.

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; these 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. Other proposed genetic modifiers that predispose Li-Fraumeni syndrome carriers to develop cancers include the MDM2-SNP309 polymorphism, shorter telomere length and increased genomic DNA copy number variation.^3,4  

A significant portion of Li-Fraumeni syndrome and, particularly, Li-Fraumeni–like (LFL) kindreds do not have demonstrable constitutional TP53 mutations. This suggests that other mechanisms disrupting normal function or defects in other genes may also be involved in familial predisposition to various cancer types.

Frequency

United States

Li-Fraumeni syndrome incidence in the general population is not well identified, but this condition is considered rare. Each year, approximately 5-10 cases of soft tissue sarcoma occur per 1 million children younger than 15 years. Of children with soft tissue sarcomas, 5-10% have family histories of malignancies consistent with Li-Fraumeni syndrome or other syndromes with an autosomal dominant inheritance pattern.

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 as high as 85%, with more than half of all tumors occurring before age 30 years.⁵ A significant proportion of affected patients, particularly children, can be successfully treated for the initial cancer but are at significant risk of subsequent development of a second primary malignancy.

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. Females affected by Li-Fraumeni syndrome have almost a 100% lifetime risk of developing cancer compared with 73% for affected males. This discrepancy may be due to the increased incidence of breast cancer in affected females. Almost 90% of affected females develop breast cancer by age 60 years with a majority occurring before age 45 years.⁶ Significantly 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 one half of the cancers occur in Li-Fraumeni syndrome family members younger than 45 years, even when members who meet clinical criteria for Li-Fraumeni syndrome are excluded.

Clinical

History

• Because of the significantly increased risk of cancer associated with Li-Fraumeni syndrome (LFS), obtaining a thorough family cancer history is very important. The history should screen for all tumor types, with particular attention to soft tissue sarcomas, osteosarcoma, 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.
• 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 have tumors with embryonic histologic findings when compared with other children (not affected by Li-Fraumeni syndrome) diagnosed with soft tissue sarcomas.⁷
• Birch et al showed that mothers of children with soft tissue sarcomas and osteosarcomas have a 3-fold increased risk of developing breast cancer at young ages.⁸

Physical

• No specific physical findings are attributed to individuals affected by Li-Fraumeni syndrome other than the findings related to the presentation of specific cancers, which are summarized as follows:
  • 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)
  • Findings of pancytopenia, including pallor, bruising, or bleeding
  • Fever (acute leukemia)
  • Signs of virilization including prepubertal genital hair, clitoromegaly or increased penile size, and acne associated with an abdominal mass (adrenal cortical carcinoma)
• Annual physical examination as part of well child care should be performed. Additional exams may be performed if symptoms arise.
• In patients with an identified p53 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.

Causes

• Inheritance of a germline mutation of the TP53 tumor suppressor gene is a predisposing genetic factor in Li-Fraumeni syndrome family members.
• A germline mutation of the checkpoint kinase gene CHK2 may be a predisposing factor in some kindred that do not have TP53 mutations.
• Other risk factors that may significantly contribute to cancer formation have not been identified.

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