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Li–Fraumeni syndrome

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Li–Fraumeni syndrome
Other namesSarcoma family syndrome of Li and Fraumeni
Li–Fraumeni syndrome is inherited via an autosomal dominant manner
SpecialtyOncology, medical genetics, neurology Edit this on Wikidata

Li–Fraumeni syndrome is a rare, autosomal dominant, hereditary disorder[1] that predisposes carriers to cancer development. It was named after two American physicians, Frederick Pei Li and Joseph F. Fraumeni Jr., who first recognized the syndrome after reviewing the medical records and death certificates of childhood rhabdomyosarcoma patients.[2]

Li-Fraumeni syndrome is caused by germline mutations (also called genetic variants) in the TP53 tumor suppressor gene,[3] which encodes a transcription factor (p53) that normally regulates the cell cycle and prevents genomic mutations. The variants can be inherited, or can arise from mutations early in embryogenesis, or in one of the parent's germ cells.

LFS is thought to occur in about 1 in 5,000 individuals in the general population. In Brazil there is a common founder variant, p.Arg337, that occurs in about 1 in every 375 people.[4]  LFS is inherited in an autosomal dominant fashion which means that a person with LFS has a 50% chance to pass the syndrome on in every pregnancy (and a 50% chance to not pass on the syndrome).[5]

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Presentation[edit]

Li–Fraumeni syndrome is characterized by early onset of cancer, a wide variety of types of cancers, and development of multiple cancers throughout one's life.[6]

Pathology[edit]

LFS1: Mutations in TP53

TP53 is a tumor suppressor gene on chromosome 17 that normally assists in the control of cell division and growth through action on the normal cell cycle. TP53 typically becomes expressed due to cellular stressors, such as DNA damage, and can halt the cell cycle to assist with either the repair of repairable DNA damage, or can induce apoptosis of a cell with irreparable damage. The repair of "bad" DNA, or the apoptosis of a cell, prevents the proliferation of damaged cells and the development of cancer.[7]

Pathogenic and likely pathogenic variants in the TP53 gene can inhibit its normal function and allow cells with damaged DNA to continue to divide. If these DNA mutations are left unchecked, some cells can divide uncontrollably, forming tumors (cancers). Many individuals with Li–Fraumeni syndrome have been shown to be heterozygous for a TP53 variant. Recent studies have shown that 60% to 80% of classic LFS families harbor detectable germ-line TP53 mutations, the majority of which are missense mutations in the DNA-binding domain.[8] These missense mutations cause a decrease in the ability of p53 to bind to DNA, thus inhibiting the normal TP53 mechanism.[9]

LFS-L:

Families who do not conform to the criteria of classical Li–Fraumeni syndrome have been termed "LFS-like".[8] LFS-like individuals generally do not have any detectable TP53 variants, and tend to meet either the Birch or Eeles criteria.

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 about 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 leukemia, lymphoma, and adrenocortical carcinoma.

About 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.

Diagnosis[edit]

Germline variants in the TP53 tumor suppressor gene was discovered to be the primary cause of Li-Fraumeni syndrome in 1990.[10][11]

Li–Fraumeni syndrome is diagnosed if a person has a pathogenic or likely pathogenic TP53 variant and/or if these three Classic Criteria are met:[12]

  • The patient has been diagnosed with a sarcoma at a young age (below 45).
  • A first-degree relative has been diagnosed with any cancer at a young age (below 45).
  • Another first- or a second-degree relative has been diagnosed with any cancer at a young age (below 45) or with a sarcoma at any age.

LFS should also be suspected in individuals who meet other published criteria.

2015 Revised Chompret Criteria:[13]

  • A proband with a tumor belonging to the LFS tumor spectrum (premenopausal breast cancer, soft tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, adrenocortical carcinoma) before age 46 years AND at least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; OR
  • A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR
  • A proband with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR
  • Breast cancer before age 31 years

Management[edit]

Genetic counseling and genetic testing are used to confirm that somebody has this gene mutation.[14]Once such a person is identified, early and regular screenings for cancer are recommended. Li-Fraumeni patients who survive their first cancers are at an increased risk to develop additional primary cancers.[14]

Recommendations[edit]

Recommendations for individuals from families affected by the syndrome include:[15]

  • Children and adults undergo comprehensive annual physical examination
  • Women undergo age-specific breast cancer monitoring beginning at age 20 years
  • All patients consult a physician promptly for evaluation of lingering symptoms and illnesses
  • Adults should undergo routine screening for colorectal cancer beginning no later than age 25 years.
  • Individuals should undergo organ-targeted surveillance based on the pattern of cancer observed in their families.
  • Avoidance of radiation therapy to increase risk of secondary radiation-induced malignancies

Suggestions[edit]

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

Epidemiology[edit]

Li–Fraumeni syndrome (LFS) is rare;[clarification needed] as of 2011, cases had been reported in more than 500 families.[8] The syndrome was discovered using an epidemiological approach. Li and Fraumeni identified four families in which siblings or cousins of rhabdomyosarcoma patients had a childhood sarcoma, which suggested a familial cancer syndrome.[16][non-primary source needed][17] Identification of TP53s the gene affected by mutation was suggested by the same approach. Over half of the cancers in LFS families had been previously associated with inactivating mutations of the p53 gene and in one primary research study, DNA sequencing in samples taken from five Li–Fraumeni syndrome families showed autosomal dominant inheritance of a mutated TP53 gene.[16][17][non-primary source needed]

See also[edit]

References[edit]

  1. ^ Custódio G; et al. (July 2013). "Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors". J. Clin. Oncol. 31 (20): 2619–26. doi:10.1200/JCO.2012.46.3711. PMC 3808236. PMID 23733769.
  2. ^ 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. S2CID 7540982.
  3. ^ 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.
  4. ^ Achatz, Maria Isabel; Zambetti, Gerard P. (2016-12). "The Inherited p53 Mutation in the Brazilian Population". Cold Spring Harbor Perspectives in Medicine. 6 (12): a026195. doi:10.1101/cshperspect.a026195. ISSN 2157-1422. {{cite journal}}: Check date values in: |date= (help)
  5. ^ de Andrade, Kelvin C.; Frone, Megan N.; Wegman-Ostrosky, Talia; Khincha, Payal P.; Kim, Jung; Amadou, Amina; Santiago, Karina M.; Fortes, Fernanda P.; Lemonnier, Nathanaël; Mirabello, Lisa; Stewart, Douglas R.; Hainaut, Pierre; Kowalski, Luiz P.; Savage, Sharon A.; Achatz, Maria I. (2019-01). "Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis". Human Mutation. 40 (1): 97–105. doi:10.1002/humu.23673. {{cite journal}}: Check date values in: |date= (help)
  6. ^ Hisada, M.; Garber, J. E.; Li, F. P.; Fung, C. Y.; Fraumeni, J. F. (1998). "Multiple Primary Cancers in Families With Li-Fraumeni Syndrome". Journal of the National Cancer Institute. 90 (8): 606–611. doi:10.1093/jnci/90.8.606. PMID 9554443.
  7. ^ Zerdoumi, Yasmine; Lanos, Raphaël; Raad, Sabine; Flaman, Jean-Michel; Bougeard, Gaëlle; Frebourg, Thierry; Tournier, Isabelle (2017-07-15). "Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage". Human Molecular Genetics. 26 (14): 2591–2602. doi:10.1093/hmg/ddx106. ISSN 0964-6906.
  8. ^ a b c Malkin, D. (2011). "Li-Fraumeni Syndrome". In Levine, Arnold J. (ed.). Genes and Cancer. Vol. 2. pp. 475–484. doi:10.1177/1947601911413466. PMC 3135649. PMID 21779515.
  9. ^ Ford, J M; Hanawalt, P C (12 September 1995). "Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance". Proceedings of the National Academy of Sciences. 92 (19): 8876–8880. doi:10.1073/pnas.92.19.8876. PMC 41070. PMID 7568035.
  10. ^ Malkin, David; Li, Frederick P.; Strong, Louise C.; Fraumeni, Joseph F.; Nelson, Camille E.; Kim, David H.; Kassel, Jayne; Gryka, Magdalena A.; Bischoff, Farideh Z.; Tainsky, Michael A.; Friend, Stephen H. (30 November 1990). "Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms". Science. 250 (4985): 1233–1238. doi:10.1126/science.1978757. PMID 1978757.
  11. ^ Srivastava, Shiv; Zou, Zhiqiang; Pirollo, Kathleen; Blattner, William; Chang, Esther H. (December 1990). "Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li–Fraumeni syndrome". Nature. 348 (6303): 747–749. doi:10.1038/348747a0. PMID 2259385.
  12. ^ Li, FrederickP.; Garber, JudyE.; Dreyfus, MargaretG.; Blattner, WilliamA.; Fraumeni, JosephF.; Sandberg, AveryA. (1990-01). "Follow-up of cancer family with in-vitro radioresistance". The Lancet. 335 (8682): 176–177. doi:10.1016/0140-6736(90)90056-b. ISSN 0140-6736. {{cite journal}}: Check date values in: |date= (help)
  13. ^ Bougeard, Gaëlle; Renaux-Petel, Mariette; Flaman, Jean-Michel; Charbonnier, Camille; Fermey, Pierre; Belotti, Muriel; Gauthier-Villars, Marion; Stoppa-Lyonnet, Dominique; Consolino, Emilie; Brugières, Laurence; Caron, Olivier; Benusiglio, Patrick R.; Bressac-de Paillerets, Brigitte; Bonadona, Valérie; Bonaïti-Pellié, Catherine (2015-07-20). "Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers". Journal of Clinical Oncology. 33 (21): 2345–2352. doi:10.1200/JCO.2014.59.5728. ISSN 0732-183X.
  14. ^ a b Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2019 Nov 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1311/
  15. ^ Kratz, Christian P.; Achatz, Maria Isabel; Brugières, Laurence; Frebourg, Thierry; Garber, Judy E.; Greer, Mary-Louise C.; Hansford, Jordan R.; Janeway, Katherine A.; Kohlmann, Wendy K.; McGee, Rose; Mullighan, Charles G.; Onel, Kenan; Pajtler, Kristian W.; Pfister, Stefan M.; Savage, Sharon A. (2017-06-01). "Cancer Screening Recommendations for Individuals with Li-Fraumeni Syndrome". Clinical Cancer Research. 23 (11): e38–e45. doi:10.1158/1078-0432.CCR-17-0408. ISSN 1078-0432.
  16. ^ a b Malkin, D.; Li, F.P.; Strong, L.C.; Fraumeni Jr, J.F.; Nelson, C.E.; Kim, D.H.; Kassel, J.; Gryka, M.A.; Bischoff, F.Z. Tainsky, M.A.; et al. (1990). "Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms". Science. 250 (4985): 1233–1238. Bibcode:1990Sci...250.1233M. doi:10.1126/science.1978757. PMID 1978757.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ a b Malkin D. & Friend, S.H. (1993). "Correction: a Li-Fraumeni syndrome p53 mutation. Erratum for "Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms"". Science. 259 (5097): 878. doi:10.1126/science.8438145. PMID 8438145. S2CID 27235459.

Further reading[edit]

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