TY  - CHAP
M1  - Book, Section
TI  - Wilms Tumor
A1  - Haber, Daniel A.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Wilms  tumor  is  a  pediatric  kidney  cancer  that  can  arise  sporadically  or  in  children  with  congenital  syndromes  conferring  genetic  susceptibility.  In  addition,  some  10  percent  of  children  with  Wilms  tumor  present  with  bilateral  cancers,  evidence  of  a  predisposing  genetic  lesion.The  genetic  loci  associated  with  the  development  of  Wilms  tumor  have  been  identified  by  analysis  of  gross  karyotype  abnormalities  in  children  with  Wilms-associated  syndromes,  as  well  as  by  molecular  analyses  of  DNA  losses  in  tumor  specimens.  A  genetic  locus  on  chromosome  11  band  p13  has  been  linked  to  Wilms  tumor  arising  in  the  context  of  aniridia  and  abnormalities  of  genitourinary  development  (e.g.,  WAGR  syndrome).  A  second  locus  on  chromosome  11  band  p15  is  associated  with  hemihypertrophy  (e.g.,  Beckwith-Wiedemann  syndrome)  and  predisposition  to  Wilms  tumor  and  other  pediatric  neoplasms.  A  third  Wilms  locus  has  been  mapped  recently  to  chromosome  17q12-21.The  WT1  gene,  mapping  within  the  11p13  genetic  locus,  was  isolated  in  1990.  It  encodes  a  transcription  factor  whose  expression  is  strictly  developmentally  regulated  in  the  normal  kidney.  Like  the  fetal  kidney  cells  from  which  they  appear  to  originate,  most  Wilms  tumors  express  high  levels  of  WT1  protein.  However,  in  a  fraction  of  Wilms  tumors,  WT1  is  either  deleted  or  mutated  to  an  inactive  form,  consistent  with  its  characterization  as  a  tumor  suppressor  gene.  Reintroduction  of  wild-type  WT1  into  a  Wilms  tumor  cell  line  with  an  aberrant  endogenous  WT1  transcript  results  in  inhibition  of  cell  growth.Inactivation  of  WT1  in  one  germ-line  allele  confers  a  high  degree  of  susceptibility  to  Wilms  tumor,  which  is  triggered  by  loss  of  the  second  WT1  allele  in  somatic  tissues.  Hemizygosity  for  WT1  in  the  germ  line  also  results  in  a  variable  degree  of  developmental  abnormalities  in  the  genitourinary  tract,  more  prominent  in  males  than  in  females.  Moreover,  specific  point  mutations  within  the  DNA-binding  domain  of  WT1  result  in  a  dominant  negative  phenotype,  characterized  by  severe  abnormalities  in  sexual  and  renal  development  (Denys-Drash  syndrome).  In  the  mouse,  hemizygous  inactivation  of  WT1  is  not  associated  with  genitourinary  defects  or  tumor  predisposition.  However,  homozygous  inactivation  of  WT1  leads  to  failure  of  renal  and  gonadal  development,  as  well  as  to  malformations  of  the  heart  and  diaphragm.The  protein  encoded  by  WT1  belongs  to  a  class  of  zinc-binding  transcription  factors,  with  multiple  variants  produced  by  alternative  splicing.  The  four  zinc-finger  domains  of  WT1  recognize  GC-rich  DNA  target  sequences,  an  effect  that  is  modulated  by  the  variable  insertion  of  three  amino  acids  (KTS)  between  zinc  fingers  3  and  4.  WT1  appears  to  function  as  a  transcriptional  repressor,  although  physiologically  relevant  target  genes  remain  to  be  defined.  Potential  protein  interactors  include  another  tumor  suppressor  gene  product,  p53,  whose  function  is  modulated  by  WT1.  Inducible  expression  of  WT1  in  tissue  culture  cells  triggers  apoptosis,  associated  with  repression  of  the  epidermal  growth  factor  receptor  and  induction  of  the  cyclin-dependent  kinase  inhibitor  p21.  Dimerization  of  WT1  may  contribute  to  the  dominant  negative  phenotype  displayed  by  mutants  with  a  disrupted  DNA-binding  domain.  Characterization  of  the  normal  pathways  involved  in  WT1  function  and  of  any  potential  interactions  with  other  Wilms  tumor  genes  may  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/16
UR  - ommbid.mhmedical.com/content.aspx?aid=1181415029
ER  -