SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer.
OBJECTIVE
Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas.


METHODS
We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas. Of these 114 patients, 89 underwent pancreaticoduodenectomy, and the somatic mutations in these cancers were correlated with patient outcome.


RESULTS
When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95% confidence interval, 1.20-3.05; P = 0.006). Patients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (> or =4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival.


CONCLUSIONS
SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas.
Blackford
Amanda
A
Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Serrano
Oscar K
OK
Wolfgang
Christopher L
CL
Parmigiani
Giovanni
G
Jones
Siân
S
Zhang
Xiaosong
X
Parsons
D Williams
DW
Lin
Jimmy Cheng-Ho
JC
Leary
Rebecca J
RJ
Eshleman
James R
JR
Goggins
Michael
M
Jaffee
Elizabeth M
EM
Iacobuzio-Donahue
Christine A
CA
Maitra
Anirban
A
Cameron
John L
JL
Olino
Kelly
K
Schulick
Richard
R
Winter
Jordan
J
Herman
Joseph M
JM
Laheru
Daniel
D
Klein
Alison P
AP
Vogelstein
Bert
B
Kinzler
Kenneth W
KW
Velculescu
Victor E
VE
Hruban
Ralph H
RH
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D017353:Gene Deletion; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D018125:Receptors, Transforming Growth Factor beta; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II