AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which patients are predisposed to cancer. LFS 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 LFS:

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- 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 LFS 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 LFS kindreds. Although osteosarcoma and chondrosarcomas occur frequently, no evidence exists of increased occurrence of Ewing sarcoma in association with LFS. Since LFS was first characterized in 1969, more than 100 LFS kindreds have been described.

Pathophysiology

LFS 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. Involvement of TP53 mutations was reported first in 1990 by Malkin et al. Subsequent studies analyzing the coding and noncoding portions of TP53 have shown that approximately 70% of LFS kindreds have constitutional (germline) mutations of 1 of the 2 copies of the TP53 tumor suppressor gene; the second copy is normal. 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 LFS. Although inactivation of TP53 confers a predisposition to cancer, this alone is not sufficient because not all families with classic LFS 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, LFS 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 LFS-associated TP53 defects involve missense point mutations occurring in a hot-spot region of exons 5-8, a portion of the gene coding 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.

A significant portion of LFS 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 a variety of cancer types. A small percentage of LFS and LFL kindreds without evidence for TP53 germline mutations have been shown to have germline mutations of the checkpoint kinase gene CHK2 localized to chromosome band 22q12. CHK2 kinase activates p53 after DNA damage. CHK2 is associated with increased incidence of certain types of cancers (like breast cancer) within the LFS/LFL kindreds.

Frequency

United States

LFS 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 LFS or other syndromes with an autosomal dominant inheritance pattern.

Mortality/Morbidity

The cancers that occur most commonly in members of LFS kindreds are breast cancer, brain tumors, acute leukemia, soft tissue sarcomas, osteosarcoma, and adrenal cortical carcinoma. A significant proportion of affected patients, particularly children, can be treated successfully for the initial cancer but are at significant risk of subsequent development of a second primary malignancy.

Race

No evidence exists of either an ethnic predisposition for LFS or an increased or decreased frequency based on nationality.

Sex

• LFS has an autosomal dominant inheritance pattern; therefore, the genetic predisposition for cancer affects males and females equally.
• Breast cancer can account for more than 40% of cancers in females affected by LFS. Other than breast cancer, no evidence exists of increased penetrance of cancer predisposition related to sex. Significantly increased occurrence of breast cancer in males of LFS kindreds is not reported.

Age

While approximately 10% of cancers occur in individuals younger than 45 years in the general population, more than one half of the cancers occur in LFS family members younger than 45 years, even when members who meet clinical criteria for LFS are excluded.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

• Because of the significantly increased risk of cancer associated with 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 LFS 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 LFS) diagnosed with soft tissue sarcomas.
• 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.

Physical

• No specific physical findings are attributed to individuals affected by LFS 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 LFS family members.
• A germline mutation of the checkpoint kinase gene CHK2 may be a predisposing factor in some kindreds that do not have TP53 mutations.
• Other risk factors that may significantly contribute to cancer formation have not been identified.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Families with LFL syndrome have (1) a proband younger than 45 years with childhood cancer or sarcoma, brain tumor, or adrenal cortical carcinoma, (2) first- or second-degree relative with a typical LFS cancer occurring at any age, and (3) another first- or second-degree relative in the lineage younger than 60 years diagnosed with any cancer. Only approximately 20% of LFL kindreds have demonstrable germline TP53 mutations. Much less stringent criteria for LFL familial cancer predisposition include 2 first- or second-degree relatives with LFS-related malignancies (sarcoma, breast cancer, malignant brain tumor, adrenal cortical carcinoma, acute leukemia) at any age.

Breast and ovarian cancer family syndrome with genetic mutations of BRCA1 or BRCA2 may be in the differential diagnosis.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Lab Studies

• Evaluation for constitutional TP53 mutation in patients with cancer and a family history or presentation suggestive of potential LFS cancer predisposition is warranted to aid in predicting future risk of other primary malignancies for the patient and other family members.
• DNA analysis
• • Although most reported LFS-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.
  • Since 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, typically collected in citrate or heparin anticoagulant tubes.

Imaging Studies

• Mammography
• • Mammography screening of females in LFS kindreds is advocated by some but remains controversial.
  • To be most effective, serial mammograms are initiated at an early age (late teens to early twenties). Some debate exists regarding the accuracy of mammographic findings in identifying small masses in the breasts of young women due to increased tissue density.
  • Experimental evidence suggests potential increased cancer risk due to increased adverse effects of ionizing radiation on LFS cells with TP53 defects.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

• No clear evidence exists that individuals with LFS diagnosed with cancers should be treated differently than other patients with cancer through the modalities of chemotherapy, radiation, or surgery. However, many studies are being conducted regarding specific mutations, in regards to prognosis and response to therapy.
• Specifics of therapy are related to the type of cancer.

Surgical Care

Prophylactic mastectomy is controversial in the LFS population and is not advocated as a reasonable surgical intervention.

Consultations

Strongly consider genetic counseling for families with LFS to ensure appropriate understanding of potential risk and possible evaluation of genetic predisposition markers.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• 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 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 LFS is controversial. Although some sources have recommended yearly complete blood counts and abdominal ultrasound in children in LFS kindreds, no evidence has been established that these or other screening tests significantly improve the ability to diagnose cancer or increase survival rates.
• • 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 LFS kindreds in whom specific constitutional TP53 mutations are documented. Due to ethical considerations, some medical genetics laboratories do not perform testing for TP53 mutations nor do they report TP53 mutations in clinically unaffected minors in families with LFS. Monitor known carriers of TP53 mutations closely.
  • Individuals who are known to be affected, either because of a history of a previous cancer consistent with LFS or because they carry a TP53 mutation, should be advised regarding the following: (1) the potential risk of the wide variety of LFS-related cancers, (2) the importance of having an established physician or other health care professional who is cognizant of the syndrome involved in ongoing care, and (3) the potential for genetic testing to evaluate potential risk for family members.
  • Individuals who are at risk based on LFS family history but who have not had cancer and for whom no TP53 mutation information is available should be monitored closely, similar to those with known predilection.

Deterrence/Prevention

• Prophylactic mastectomy decreases the risk of only one type of cancer in women at high risk for several other potentially deadly malignancies.

Prognosis

• Children in families with LFS 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. LFS patients have a predilection for developing subsequent primary tumors (especially sarcomas) in prior radiation fields.
• Cumulative probability of a person affected by LFS developing a second cancer is 57% at 30 years after developing the first cancer.

Patient Education

• Genetic counseling for at-risk individuals in families with LFS 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 LFS who are treated successfully for cancer must understand the significant risk of developing further primary malignancies and the need for close medical follow-up care.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Obtaining a thorough family history with particular emphasis on cancer can be tedious but is an important part of the evaluation of every child diagnosed with a malignancy. Families in which predisposition for cancers is evident should have access to genetic counseling to help provide them with appropriate assessment of risk, delineation of possible interventions or behaviors that can affect risk, and assistance in dealing with the emotional stress associated with the potential of developing cancer.
• Testing for germline TP53 mutations is available, but considerations should be made regarding its use. Use of this test a general screening evaluation in patients with cancer is very limited; however, patients and families with histories consistent with LFS or with presentations of cancer suggestive of a possible germline TP53 mutation should be counseled regarding the accessibility of testing.
• • Initially, testing should be limited to an affected individual (ie, in whom cancer has been diagnosed) to determine if a TP53 mutation exists. Then, subsequent testing of at-risk family members can be limited to the specific mutation previously documented. Most clinical laboratories do not test family members who are minors if they do not have cancer.
  • Prior to testing, ensure that the significance of either a positive or 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 risk may depend on health-related behaviors (eg, cigarette smoking, diet) and other potential genetic factors.
• Patients in families with LFS who are treated for cancer must be counseled regarding the significant risk of developing other primary malignancies and appropriate follow-up monitoring.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jul 12, 2006