Li–Fraumeni syndrome

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Li–Fraumeni syndrome
Classification and external resources
ICD-9 758.3
OMIM 151623
DiseasesDB 7450
eMedicine ped/1305
MeSH D016864

Li–Fraumeni syndrome is an extremely rare autosomal dominant hereditary disorder. Named after Frederick Pei Li and Joseph F. Fraumeni, Jr., the American physicians who first recognized and described the syndrome,[1] Li–Fraumeni syndrome greatly increases susceptibility to cancer. This syndrome is also known as the Sarcoma, breast, leukaemia and adrenal gland (SBLA) syndrome.

The syndrome is linked to germline mutations of the TP53 tumor suppressor gene,[2] which normally helps control cell growth. The mutations can be inherited or can arise de novo early in embryogenesis or in one of the parent's germ cells.

The TP53 gene is responsible for initiating DNA repair mechanisms and/or apoptosis upon detection of DNA damage. P53 is a dominant negative mutation, so the mutant protein can inactivate the normal protein, meaning the mutant protein is dominant. Because of this, Li–Fraumeni syndrome, with one of the two p53 copies already mutated, predisposes a person to cancer development. Persons with Li–Fraumeni syndrome have an approximately 25-fold increased risk of developing a malignant tumor by age 50 than the population average, and 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.[3]

Characteristics[edit]

Li–Fraumeni syndrome is characterised by:

  • several kinds of cancer are involved;
  • cancer often appears at a young age; and,
  • cancer often appears several times throughout the life of an affected person.

Epidemiology[edit]

This syndrome is considered rare with ~400 individuals from 64 families reported in the literature.[citation needed] Its true incidence is unknown.

The frequency of new (de novo) TP53 mutations is estimated to be at least 7% and may be as high as 20%.[4]

Pathology[edit]

  • LFS1: The TP53 (tumor suppressor gene p53) normally assists in the control of cell division and growth through action on the normal cell cycle. TP53 assists in repair or destruction of "bad" DNA before it can enter the normal cell cycle, thus preventing abnormal and/or cancerous growth of cells. Mutations of TP53 prevent this normal function and allow damaged cells to divide and grow in an uncontrolled, unchecked manner forming tumors (cancers). TP53 mutations have been primarily implicated in Li–Fraumeni. There are 11 exons in the gene. 70% of cases have mutations in exons 5-8. An additional 25% have mutations in either exon 4 or 9. 75% of the mutations reported at missense mutations resulting in premature stop codons and a truncated protein.
  • LFS2: A variant of Li–Fraumeni does not have a mutation in TP53 but instead has mutation of the CHEK2 (or CHK2) gene. CHK2 is also a tumor suppressor gene. CHK2 regulates the action of p53. CHK2 is activated by ATM which detects DNA damage, and in this way DNA damage information can be conveyed to p53 to indirectly arrest the cell cycle at that point for DNA repair to be able to take place or to cause apoptosis (programmed cell death).
  • A third locus has been mapped to the long arm of chromosome 1 (1q23) but no gene has yet been identified.

Most of these mutations in p53 are located in DNA binding domain of the protein and have a dominant-negative effect over alternate wild type alleles.

Clinical[edit]

The classical LFS malignancies - sarcoma, cancers of the breast, brain and adrenal glands - comprise about 80% of all cancers that occur in this syndrome.

The risk of developing any invasive cancer (excluding skin cancer) is ~50% by age 30 (1% in the general population) and is 90% by age 70. Early onset breast cancer accounts for 25% of all the cancers in this syndrome. This is followed by soft tissue sarcomas (20%), bone sarcoma (15%) and brain tumors - especially glioblastomas - (13%). Other tumours seen in this syndrome include leukaemia, lymphoma and adrenocortical carcinoma.

~90% of females with LFS develop breast cancer by age 60 years; the majority of these occur before age 45 years. Females with this syndrome have almost a 100% lifetime risk of developing cancer. This compares with 73% for affected males. The difference may be due to much smaller breast tissue in males as well as increased estrogen levels in females.

The risks of sarcoma, female breast cancer and haematopoietic malignancies in mutation carriers are more than 100 times greater than those seen in the general population.

Other tumours reported in this syndrome but not yet proved to be linked with it include melanoma, Wilm's and other kidney tumors, gonadal germ cell, pancreatic, gastric, choroid plexus, colorectal and prostate cancers.

80% of children with adrenocortical carcinoma and 2%-10% of childhood brain tumors have p53 mutations.

2%-3% of osteosarcomas, 9% rhabdomyosarcomas and 7%-20% patients with multiple primary tumors have p53 mutations.

Although most cases of this syndrome have early onset of cancer, cases have also been reported later in life.[5]

Diagnosis[edit]

Li–Fraumeni syndrome is diagnosed if the following three criteria are met:

  1. the patient has been diagnosed with a sarcoma at a young age (below 45),
  2. a first-degree relative has been diagnosed with any cancer at a young age (below 45),
  3. and another first-degree or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age.

Other criteria have also been proposed:

The Birch criteria[6]

  1. a proband with any childhood cancer or sarcoma, brain tumor or adrenal cortical carcinoma diagnosed before age 45
  2. a first or second degree relative with a typical LFS malignancy (sarcoma, leukaemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis
  3. a first or second degree relative with any cancer diagnosed before age 60

The Eeles criteria[7]

  1. two first or second degree relatives with LFS-related malignancies at any age

Management[edit]

Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation. Once such a person is identified, early and regular screenings for cancer are recommended for him or her as people with Li–Fraumeni are likely to develop another primary malignancy at a future time (57% within 30 years of diagnosis).

Chompret criteria[edit]

The Chompret criteria for screening are[8]

A proband who has:

  • tumor belonging to the LFS tumor spectrum - soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia or lung bronchoalveolar cancer - before age 46 years;

and at least one of the following

  • at least one first or second degree relative with an LFS tumour (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumours
  • a proband with multiple tumours (except multiple breast tumours), two of which belong to the LFS tumour spectrum and the first of which occurred before age 46 years
  • a proband who is diagnosed with adrenocortical carcinoma or choroid plexus tumour, irrespective of family history

Recommendations[edit]

  • Avoidance of radiation therapy to reduce risk of secondary radiation induced malignancies
  • Children and adults undergo comprehensive annual physical examination
  • Women undergo age specific breast cancer monitoring beginning at age 25 years
  • All patients should consult a physician promptly for evaluation of lingering symptoms and illnesses

Suggestions[edit]

  • Adults undergo routine screening for colorectal cancer beginning no later than age 25 years
  • Individuals undergo organ targeted surveillance based on the pattern of cancer observed in their family

Prophylactic mastectomy to reduce the risk of breast cancer is an option.

See also[edit]

References[edit]

  1. ^ Li F.P., Fraumeni J.F. (October 1969). "Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?". Ann. Intern. Med. 71 (4): 747–52. doi:10.7326/0003-4819-71-4-747. PMID 5360287. 
  2. ^ Varley J.M. (March 2003). "Germline TP53 mutations and Li-Fraumeni syndrome". Hum. Mutat. 21 (3): 313–20. doi:10.1002/humu.10185. PMID 12619118. 
  3. ^ Ramzi Cotran, Vinay Kumar, Tucker Collins (2010). Robbins Pathologic Basis of Disease, 8th Edition. W.B. Saunders. pp. 288–290. ISBN 1-4377-0792-0. 
  4. ^ Gonzalez KD, Buzin CH, Noltner KA, Gu D, Li W, Malkin D, Sommer SS. (2009) High Frequency of de novo mutations in Li-Fraumeni syndrome. Med Genet. 46(10):689-93
  5. ^ Cho Y, Kim J, Kim Y, Jeong J, Lee KA (2013) A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer. Ann Lab Me 33(3):212-216. doi: 10.3343/alm.2013.33.3.212
  6. ^ Birch JM, Hartley AL, Tricker K, Prosser J, Condie A, Kelsey A, Harries M, Jones P, Binchy A, Crowther D, Craft A, Eden O, Evans D, Thompson E, Mann J, Martin J, Mitchell E, Santibanez-Koref M (1994) Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 54:1298–304
  7. ^ Eeles R (1995) Germline mutations in the TP53 gene. Cancer Surv 25:101–124
  8. ^ Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, Bonaiti-Pellie C, Stoppa-Lyonnet D (2009) Version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 27:1–2

External links[edit]