Genetic Mutations Associated with Cigarette Smoking in Pancreatic Cancer

被引:98
作者
Blackford, Amanda [2 ]
Parmigiani, Giovanni [1 ,2 ,5 ]
Kensler, Thomas W. [6 ]
Wolfgang, Christopher [3 ]
Jones, Sian [2 ]
Zhang, Xiaosong [2 ]
Parsons, D. Willams [2 ]
Lin, Jimmy Cheng-Ho [2 ]
Leary, Rebecca J. [2 ]
Eshleman, James R. [1 ,2 ]
Goggins, Michael [1 ,2 ,4 ]
Jaffee, Elizabeth M. [1 ,2 ]
Iacobuzio-Donahue, Christine A. [1 ,2 ]
Maitra, Anirban [2 ,4 ]
Klein, Alison [1 ,2 ,7 ]
Cameron, John L. [3 ]
Olino, Kelly [3 ]
Schulick, Richard [3 ]
Winter, Jordan [3 ]
Vogelstein, Bert [1 ,2 ]
Velculescu, Victor E. [2 ]
Kinzler, Kenneth W. [2 ]
Hruban, Ralph H. [1 ,2 ]
机构
[1] Johns Hopkins Med Inst, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA
[2] Johns Hopkins Med Inst, Dept Oncol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA
[3] Johns Hopkins Med Inst, Dept Surg, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA
[4] Johns Hopkins Med Inst, Dept Med, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21231 USA
[5] Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA
[6] Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA
[7] Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA
关键词
RAS ONCOGENE ACTIVATION; SELF-REPORTED SMOKING; K-RAS; RISK-FACTORS; HOMOZYGOUS DELETIONS; SOMATIC MUTATIONS; SUPPRESSOR GENE; TOBACCO-SMOKE; P53; MUTATIONS; LUNG CANCERS;
D O I
10.1158/0008-5472.CAN-09-0015
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cigarette smoking doubles the risk of pancreatic cancer, and smoking account: 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 by 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 carcinoma; 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. [Cancer Res 2009;69(8):3681-8]
引用
收藏
页码:3681 / 3688
页数:8
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