TY  - CHAP
M1  - Book, Section
TI  - Tumor-Suppressor Genes
A1  - Fearon, Eric R.
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  - Cancers  arise  as  the  result  of  an  accumulation  of  inherited  and  somatic  mutations  in  proto-oncogenes  and  tumor-suppressor  genes.  In  contrast  to  the  activating  mutations  that  generate  oncogenic  alleles  from  proto-oncogenes,  tumor-suppressor  genes  are  targeted  by  loss-of-function  mutations  in  cancer  cells.  A  third  class  of  mutated  genes,  with  a  rather  more  indirect  role  in  cancer  initiation  and  progression,  has  been  identified;  namely,  the  DNA-repair-pathway  genes.  Their  inactivation  in  cancer  is  presumed  to  contribute  to  the  development  of  mutations  in  other  genes  that  directly  affect  cell  proliferation  and  survival,  such  as  the  oncogenes  and  tumor-suppressor  genes.  Because  DNA-repair  genes  are  affected  by  loss-of-function  mutations  in  cancer,  they  are  often  considered  to  represent  a  subset  of  the  tumor-suppressor  genes.While  a  number  of  relatively  straightforward  approaches  have  enabled  the  identification  of  oncogenic  alleles  in  cancer,  identification  of  tumor-suppressor  genes  has  proven  more  difficult.  Somatic  cell  genetic  studies  provided  early  evidence  that  tumorigenicity  was  a  recessive  trait  in  many  cancers.  Based  on  such  findings,  the  existence  of  tumor-suppressor  genes  was  inferred.  The  somatic  cell  genetic  approaches  have  provided  a  means  to  define  specific  chromosomal  regions  containing  tumor-suppressor  genes,  even  though  few  tumor-suppressor  genes  have  been  identified  using  the  approaches.Knudson's  epidemiologic  studies  of  retinoblastoma  led  to  a  proposal  that  has  subsequently  been  termed  the  “two-hit  hypothesis.”  In  brief,  Knudson  proposed  that  two  inactivating  mutations  were  necessary  for  retinoblastoma  development.  The  first  mutation  at  the  retinoblastoma  susceptibility  locus  could  be  either  a  germ  line  or  somatic  mutation,  while  the  second  mutation  was  always  somatic.  Knudson's  hypothesis  not  only  illustrated  the  mechanisms  through  which  inherited  and  somatic  mutations  might  collaborate  in  tumorigenesis,  but  it  linked  the  notion  of  recessive  genetic  determinants  for  cancer  susceptibility  to  the  findings  from  the  somatic  cell  genetic  studies.To  date,  more  than  20  tumor-suppressor  genes  have  been  localized  and  identified  through  various  experimental  approaches,  often  employed  in  concert.  The  approaches  include  cytogenetic  studies  of  constitutional  chromosomal  alterations  in  cancer  patients,  linkage  analyses  to  localize  genes  that  predispose  to  cancer,  and  loss  of  heterozygosity  (LOH)  or  allelic  loss  studies  undertaken  on  matched  pairs  of  normal  and  cancer  tissue.The  authenticity  of  a  tumor-suppressor  gene  is  most  clearly  established  by  the  identification  of  inactivating  germ  line  mutations  that  segregate  with  cancer  predisposition,  coupled  with  the  identification  of  somatic  mutations  inactivating  the  wild-type  allele  in  the  cancers  arising  in  those  with  a  germ  line  mutation.  Supportive,  but  less  convincing,  evidence  of  a  tumor-suppressor  role  for  other  genes  may  be  presented,  such  as  the  identification  of  somatic,  inactivating  mutations  in  a  gene  in  one  or  more  types  of  cancer,  or  its  decreased  or  absent  expression  in  cancers.  Largely  because  of  the  difficulties  in  assigning  causal  significance  to  any  gene  solely  based  on  somatic  alterations  in  its  sequence  and/or  expression  in  cancers,  genes  not  affected  by  inactivating,  germ  line  mutations  are  most  appropriately  considered  as  candidate  tumor-suppressor  genes  until  additional  data  are  available.Powerful  insights  into  the  cellular  functions  of  many  tumor-suppressor  proteins,  such  as  pRb,  p16,  p53,  and  APC,  have  been  obtained.  It  has  become  apparent  that  tumor-suppressor  proteins  function  in  a  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/16
UR  - ommbid.mhmedical.com/content.aspx?aid=1181413729
ER  -