RT Book, Section
A1 Shi, Dr. Chanjuan
A1 Hruban, Dr. Ralph H.
A1 Kern*, Dr. Scott E.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181416878
T1 Pancreatic 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=1181416878
RD 2024/04/19
AB Pancreatic  cancer  is  the  fourth  leading  cause  of  cancer  death  in  the  United  States,  with  an  estimated  38,000  American  deaths  in  2013.  Worldwide  it  causes  approximately  227,000  deaths  each  year  and  is  the  eighth  most  common  cause  of  cancer-related  death.  The  major  type,  pancreatic  ductal  adenocarcinoma,  is  a  nearly  uniformly  metastatic  and  fatal  disease,  and  the  mortality  rate  for  pancreatic  ductal  adenocarcinoma  closely  follows  that  of  the  incidence.  Pancreatic  cancer  presents  clinically  with  pain,  with  symptoms  related  to  obstruction  of  the  biliary  or  pancreatic  ducts,  or  with  protean  symptoms  such  as  weight  loss  and  cachexia.  Pancreatic  neuroendocrine  tumor  is  a  separate  major  category  of  pancreatic  neoplasms,  often  has  endocrine  clinical  sequelae,  and  is  less  frequently  metastatic  and  fatal.Although  most  carcinomas  of  the  pancreas  appear  to  be  sporadic,  studies  suggest  that  3-10%  of  all  cases  of  pancreatic  ductal  adenocarcinoma  are  hereditary.  Some  of  the  genes  responsible  for  the  familial  aggregation  of  pancreatic  cancer  are  known,  and  they  most  convincingly  include  germline  mutations  in  the  BRCA2,  PALB2,  CDKN2A,  PRSS1,  ATM,  STK11/LKB1,  and  DNA  mismatch-repair  genes.The  profile  of  somatic  genetic  mutations  in  pancreatic  cancer  is  distinct  from  other  neoplasms.  The  KRAS  oncogene  is  commonly  activated  by  somatic  mutations  in  pancreatic  cancer,  whereas  three  tumor-suppressor  genes  are  commonly  inactivated.  Ninety  percent  or  more  of  pancreatic  cancers  harbor  activating  point  mutations  in  codon  12  of  KRAS.  The  CDKN2A  tumor-suppressor  gene  is  inactivated  in  90-100%  of  pancreatic  cancers,  TP53  in  75%,  and  SMAD4  in  50%.  In  addition,  recurrent  somatic  mutations  of  the  MKK4,  STK11/LKB1,  TGFβ  receptors,  Smad  and  Fanconi  anemia  pathways,  ATM,  and  ARID1A  genes  have  also  been  reported.  Various  loci  of  gene  amplifications  each  affect  a  minority  of  carcinomas.Inactivation  of  the  SMAD4  gene  may  be  rather  specific  for  pancreatic  ductal  adenocarcinoma.  SMAD4  is  inactivated  in  as  few  as  15%  of  metastatic  colorectal  cancers  and  in  less  than  10%  of  other  major  cancer  types.  SMAD4  belongs  to  a  class  of  proteins  that  mediate  signals  of  the  TGF-β  superfamily.Microsatellite  instability  (RER+)  is  seen  in  a  small  minority  (~  4%)  of  pancreatic  cancers.  These  RER+  cancers  have  a  characteristic  histologic  appearance  (medullary  histology)  and  frequently  have  wild-type  KRAS  gene.The  diagnosis  of  pancreatic  cancer  is  suspected  based  on  clinical  findings,  and  often  can  be  confirmed  with  radiologic  and  endoscopic  techniques.  Effective  screening  tests  are  not  available  yet.  However,  DNA-based  testing  appears  promising.Recently,  the  exomes  of  the  four  most  common  cystic  neoplasms  of  the  pancreas  have  been  sequenced,  and  each  cyst  type  has  its  own  unique  mutational  profile.  Serous  cystic  neoplasms  are  characterized  by  VHL  mutations,  solid-pseudopapillary  neoplasms  harbor  CTNNB1mutations,  intraductal  papillary  mucinous  neoplasms  have  GNAS,  RNF43,  KRAS,  and,  in  advanced  cases,  TP53  and  SMAD4  gene  mutations,  and  mucinous  cystic  neoplasms  have  RNF43,  KRAS,  and,  in  advanced  cases,  TP53  and  SMAD4  alterations.DAXX,  ATRX,  MEN-1  and  mTOR  pathway  genes  are  mutated  in  pancreatic  neuroendocrine  tumors.