TY  - CHAP
M1  - Book, Section
TI  - Li-Fraumeni Syndrome
A1  - Malkin, David
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.338
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - The  Li-Fraumeni  syndrome  (LFS)  is  a  rare  autosomal  dominantly  inherited  disorder.  It  is  characterized  by  the  diagnosis  of  bone  or  soft  tissue  sarcoma  at  an  early  age  in  an  individual  who  has  one  first-degree  relative  with  early  onset  cancer  and  a  second  close  relative  with  early  onset  cancer  or  sarcoma  diagnosed  at  any  age.Families  in  which  the  classic  phenotype  of  the  syndrome  is  not  expressed  completely  are  termed  Li-Fraumeni  syndrome-like  (LFS-L)  and  are  represented  by  many  different  features.  Common  to  all  these  families  is  the  occurrence  of  a  variety  of  cancers  of  a  distinct  histopathologic  type.Germ-line  alterations  of  the  p53  tumor-suppressor  gene  located  on  chromosome  17p13  have  been  observed  in  the  majority  of  LFS  families  and  in  a  proportion  of  LFS-L  families.  This  gene  encodes  a  53-kDa  nuclear  phosphoprotein  that  is  composed  of  393  amino  acids.  Genetic  alterations  primarily  result  from  base-pair  substitutions  that  result  in  missense  mutations.  These  changes  are  among  the  most  frequently  observed  genetic  abnormalities  in  human  cancer.  Somatic  inactivation  of  p53  occurs  through  base-pair  substitutions  or  binding  to  other  cellular  proteins  or  to  certain  DNA  tumor  virus  proteins.The  p53  protein  binds  specific  DNA  sequences  and  appears  to  be  a  transcription  factor  that  may  regulate  the  expression  of  other  growth  regulatory  genes  in  a  positive  or  negative  manner.  The  antiproliferative  effect  of  wild-type  p53  is  exerted  at  a  checkpoint  control  site  before  G1/S  of  the  cell  cycle,  with  G2/M  and  the  mitotic  spindle  being  other  potential  targets.  p53  mediates  apoptosis  and  plays  an  important  role  in  modulating  the  cellular  response  to  DNA  damage  induced  by  ultraviolet  (UV)  irradiation  or  γ-irradiation  and  certain  chemotherapeutic  agents.p53  mutations  are  not  observed  in  all  classic  LFS  families.  Germ-line  p53  mutations  are  seen  in  a  small  number  of  patients  and  families  with  cancer  phenotypes  that  only  superficially  resemble  LFS.  Other  mechanisms  of  p53  inactivation  may  occur  in  some  clinical  settings,  and  other  genes  involved  in  cell  cycle  regulation  may  be  altered  in  p53  wild-type  families.Mouse  models  of  p53  deficiency  have  been  created.  These  p53  knockouts  exhibit  an  increased  rate  of  development  of  a  spectrum  of  tumors,  including  lymphomas  and  sarcomas.  Transgenic  p53  mice  have  been  generated  that  have  a  tumor  phenotype  distinct  from  that  of  the  p53-deficient  animals.  Mice  heterozygous  for  a  deleted  p53  allele  exhibit  an  intermediate  phenotype  in  that  the  rate  of  tumor  formation  is  slower  than  that  of  the  p53-null  animals  yet  faster  than  that  of  wild-type  littermates.  These  mice  have  been  used  as  in  vivo  models  to  analyze  p53  function  and  dysfunction  in  the  setting  of  interventions  with  chemotherapy,  radiation  therapy,  or  teratogenic  agents.Predictive  genetic  testing  for  carriers  of  mutant  p53  is  available  in  research  settings  in  a  few  centers.  The  interpretation  of  results  with  respect  to  diagnostic  capabilities  and  options  for  therapeutic  intervention  is  under  scrutiny.  The  value  of  such  screening  is  tempered  by  the  need  to  evaluate  risk,  counseling  issues,  the  need  for  informed  consent,  and  regulations  on  testing.  
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.338
Y2  - 2024/04/18
UR  - ommbid.mhmedical.com/content.aspx?aid=1181414968
ER  -