RT Book, Section
A1 Feinberg, Andrew P.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181403595
T1 Genomic Imprinting and Cancer
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181403595
RD 2024/04/19
AB Genomic  imprinting  is  an  epigenetic  modification  of  a  specific  parental  allele  of  a  gene,  or  the  chromosome  on  which  it  resides,  in  the  gamete  or  zygote  leading  to  differential  expression  of  the  two  alleles  of  the  gene  in  somatic  cells  of  the  offspring.Evidence  for  genomic  imprinting  in  normal  development  derives  from  studies  over  many  years  of  the  whole  genome,  specific  chromosomal  regions,  and  individual  imprinted  loci.  There  is  now  an  intense  search  for  an  ever-increasing  list  of  imprinted  genes  that  are  involved  in  many  different  types  of  cellular  processes.Genomic  imprinting  challenges  two  assumptions  of  Mendelian  genetics  applied  to  human  disease:  that  the  maternal  and  paternal  alleles  of  a  gene  are  equivalent  and  that  two  functional  copies  of  a  gene  always  are  associated  with  health.  Imprinted  genes  probably  account  for  many  examples  of  developmental  malformations  in  humans.Hydatidiform  moles  and  complete  ovarian  teratomas,  the  genome  of  each  of  which  is  derived  from  a  single  parental  origin,  show  that  an  imbalance  of  maternal  and  paternal  genome  equivalents  leads  to  neoplastic  growth.Several  chromosomes  show  parental  origin-specific  alterations  in  cancer,  including  losses  of  heterozygosity  in  Wilms  tumor  and  in  acute  myelocytic  leukemia  and  gene  amplification  in  neuroblastoma.Beckwith-Wiedemann  syndrome,  a  disorder  of  prenatal  overgrowth  and  cancer,  sometimes  involves  parental  origin-specific  germ-line  chromosomal  rearrangements  and  uniparental  disomy.Loss  of  imprinting  (LOI)  is  a  recently  discovered  alteration  in  cancer  that  involves  loss  of  parental  origin-specific  gene  expression.  LOI  may  include  activation  of  the  normally  silent  copy  of  growth-promoting  genes  and/or  silencing  of  the  normally  transcribed  copy  of  tumor  suppressor  genes.  These  changes  can  involve  a  switch  of  a  maternal  chromosome  to  a  paternal  epigenotype.There  is  a  rapidly  increasing  number  of  examples  of  genes  and  tumors  that  show  LOI.  Genes  include  IGF2,  H19,  and  p57KIP2.  Tumors  include  Wilms  tumor;  hepatoblastoma;  rhabdomyosarcoma;  Ewing  sarcoma;  uterine,  cervical,  esophageal,  prostate,  lung,  and  colon  cancer;  choriocarcinoma;  and  germ-cell  tumors.  Thus  LOI  is  one  of  the  most  common  alterations  in  human  cancer.Normal  genomic  imprinting  is  maintained  in  part  by  parental  origin-specific,  tissue-independent  DNA  methylation  of  cytosine  within  CpG  islands,  regions  rich  in  CpG  dinucleotides.  Tumors  with  LOI  show  abnormal  methylation  of  these  CpG  islands.Normal  genomic  imprinting  should  be  viewed  as  a  developmental  process  rather  than  as  a  single  event.  Thus  a  combination  of  both  cis-acting  and  trans-acting  signals  is  likely  to  be  important  in  the  establishment  and  maintenance  of  normal  genomic  imprinting,  and  disruption  of  these  same  factors  can  be  expected  to  play  a  role  in  LOI  in  cancer.Since  normal  imprinting  is  reversible,  LOI  also  may  be  reversible  and  amenable  to  novel  therapeutic  approaches,  such  as  modification  with  5-aza-2′-deoxycytidine,  an  inhibitor  of  DNA  methylation.