Excerpt from Li-Fraumeni Syndrome

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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.

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