What is the pathophysiology of Li-Fraumeni syndrome?

Updated: Nov 13, 2018
  • Author: ; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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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. [10] 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. [1]

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. [12]

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. [17]


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