Genetic mutations associated with cigarette smoking in pancreatic cancer.
Cigarette smoking doubles the risk of pancreatic cancer, and smoking accounts for 20% to 25% of pancreatic cancers. The recent sequencing of the pancreatic cancer genome provides an unprecedented opportunity to identify mutational patterns associated with smoking. We previously sequenced >750 million bp DNA from 23,219 transcripts in 24 adenocarcinomas of the pancreas (discovery screen). In this previous study, the 39 genes that were mutated more than once in the discovery screen were sequenced in an additional 90 adenocarcinomas of the pancreas (validation screen). Here, we compared the somatic mutations in the cancers obtained from individuals who ever smoked cigarettes (n = 64) to the somatic mutations in the cancers obtained from individuals who never smoked cigarettes (n = 50). When adjusted for age and gender, analyses of the discovery screen revealed significantly more nonsynonymous mutations in the carcinomas obtained from ever smokers (mean, 53.1 mutations per tumor; SD, 27.9) than in the carcinomas obtained from never smokers (mean, 38.5; SD, 11.1; P = 0.04). The difference between smokers and nonsmokers was not driven by mutations in known driver genes in pancreatic cancer (KRAS, TP53, CDKN2A/p16, and SMAD4), but instead was predominantly observed in genes mutated at lower frequency. No differences were observed in mutations in carcinomas from the head versus tail of the gland. Pancreatic carcinomas from cigarette smokers harbor more mutations than do carcinomas from never smokers. The types and patterns of these mutations provide insight into the mechanisms by which cigarette smoking causes pancreatic cancer.
Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Amanda
A
Blackford
Giovanni
G
Parmigiani
Thomas W
TW
Kensler
Christopher
C
Wolfgang
Siân
S
Jones
Xiaosong
X
Zhang
D Willams
DW
Parsons
Jimmy Cheng-Ho
JC
Lin
Rebecca J
RJ
Leary
James R
JR
Eshleman
Michael
M
Goggins
Elizabeth M
EM
Jaffee
Christine A
CA
Iacobuzio-Donahue
Anirban
A
Maitra
Alison
A
Klein
John L
JL
Cameron
Kelly
K
Olino
Richard
R
Schulick
Jordan
J
Winter
Bert
B
Vogelstein
Victor E
VE
Velculescu
Kenneth W
KW
Kinzler
Ralph H
RH
Hruban
D000368:Aged; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics*