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Li–Fraumeni syndrome

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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
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 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

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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

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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

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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

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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

Birch Criteria for Li Fraumeni-like syndrome:[14]

  • A proband with any childhood cancer, sarcoma, brain tumor, or adrenal cortical carcinoma diagnosed before age 45, AND
  • A first- or second-degree relative with a typical LFS malignancy (sarcoma, leukemia, or cancers of the breast, brain or adrenal cortex) regardless of age at diagnosis, AND
  • A first- or second-degree relative with any cancer diagnosed before age 60

Eeles Criteria for Li Fraumeni-like Syndrome:

  • Two different tumors that are part of extended LFS in first- or second-degree relatives at any age (sarcoma, breast cancer, brain tumor, leukemia, adrenocortical carcinoma, melanoma, prostate cancer, and pancreatic cancer).

If an individual has a personal and/or family history concerning for LFS, they should discuss the risks, benefits, and limitations of genetic testing with their healthcare provider or a genetic counselor.

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Management

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Genetic counseling and genetic testing for the TP53 gene can confirm a diagnosis of LFS.[15] People with LFS require early and regular cancer screening following the "Toronto Protocol": [16][17][15]

  • Children and adults undergo comprehensive annual physical examination every 6-12 months
  • All patients consult a physician promptly for evaluation of lingering symptoms and illnesses
  • Ultrasound of abdomen and pelvis every 3-4 months birth to age 18 years
  • Colonoscopy and upper endoscopy every 2-5 years beginning at age 25 or 5 years before the earliest known GI cancer in the family
  • Annual dermatological exam starting at age 18 years
  • Annual whole-body MRI
  • Annual brain MRI and neurological exam
  • Annual prostate-specific antigen (PA) starting at age 40
  • Breast awareness beginning at age 18
  • Clinical breast exam every 6-12 months starting at age 20
  • Annual breast MRI age 20-29; annual breast MRI alternating with mammogram age 30-75
  • Consideration of risk-reducing mastectomy (surgery to remove the breast tissue)

Additional Resources

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GeneReviews - Li-Fraumeni Syndrome[18]

References

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  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. (December 2016). "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. PMID 27663983.
  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. (January 2019). "Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis". Human Mutation. 40 (1): 97–105. doi:10.1002/humu.23673. PMC 6296902. PMID 30352134.
  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 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. (January 1990). "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. PMID 1967474.
  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. PMID 26014290.
  14. ^ Birch, JM; Heighway, J; Teare, MD; Kelsey, AM; Hartley, AL; Tricker, KJ; Crowther, D; Lane, DP; Santibáñez-Koref, MF (December 1994). "Linkage studies in a Li-Fraumeni family with increased expression of p53 protein but no germline mutation in p53". British Journal of Cancer. 70 (6): 1176–1181. doi:10.1038/bjc.1994.468. ISSN 0007-0920. PMC 2033684. PMID 7981072.
  15. ^ a b 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. ^ Villani, Anita; Shore, Ari; Wasserman, Jonathan D; Stephens, Derek; Kim, Raymond H; Druker, Harriet; Gallinger, Bailey; Naumer, Anne; Kohlmann, Wendy; Novokmet, Ana; Tabori, Uri; Tijerin, Marta; Greer, Mary-Louise C; Finlay, Jonathan L; Schiffman, Joshua D (September 2016). "Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study". The Lancet Oncology. 17 (9): 1295–1305. doi:10.1016/S1470-2045(16)30249-2. PMID 27501770.
  17. ^ Vogel, Wendy H. (2017). "Li-Fraumeni Syndrome". Journal of the Advanced Practitioner in Oncology. 8 (7): 742–746. ISSN 2150-0878. PMC 6188099. PMID 30333936.
  18. ^ Schneider, Katherine; Zelley, Kristin; Nichols, Kim E.; Garber, Judy (1993), Adam, Margaret P.; Feldman, Jerry; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Li-Fraumeni Syndrome", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID 20301488, retrieved 2024-07-02

Further reading

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