[1396] Genetic Mutations Associated with Cigarette Smoking in Pancreatic Cancer

A Blackford, G Parmigiani, T Kensler, CL Wolfgang, S Jones, X Zhang, DW Parsons, JC Lin, RJ Leary, J Eshleman, M Goggins, EM Jaffee, CA Iacobuzio-Donahue, SE Kern, A Maitra, JL Cameron, K Olino, RD Schulick, J Winter, B Vogelstein, VE Velculescu, KW Kinzler, RH Hruban. The Johns Hopkins Medical Institutions, Baltimore, MD

Background: Cigarette smoking doubles the risk of pancreatic cancer and it has been estimated that smoking accounts for 20 to 25% of pancreatic cancers. The recent sequencing of the pancreatic cancer genome (Jones et al Science 2008) provides an unprecedented opportunity to identify the genetic mutations associated with smoking.
Design: We previously sequenced over 750,000,000 base pairs of DNA from 23,219 transcripts, representing 20,661 protein-coding genes in a series of 24 pancreatic cancers. The number and types of non-synonymous somatic mutations in the cancers obtained from individuals who ever smoked cigarettes (n=11) were compared to the number and types of non-synonymous somatic mutations in the cancers obtained from individuals who never smoked cigarettes (n=13). Mutations were also correlated with other clinical parameters.
Results: More mutations were identified in the carcinomas obtained from ever smokers than in the carcinomas obtained from never smokers, in high-grade carcinomas than moderate grade carcinomas, in carcinomas obtained from patients 70 years of age than those obtained from patients <70, and in carcinomas obtained from men than women.

Mutations Per Tumor

	N	Mean (SD)	Adjusted p value*
Non-smoker	13	41.4(11.5)	0.07
Smoker	11	56.8(30.9)
Age <70	16	45.1(14.7)	0.30
Age 70+	8	55.2(35.3)
Black	3	44.3(9.9)	0.75
White	21	49(24.8)
Female	10	42.2(9.6)	0.22
Male	14	52.9(29.1)
Moderate Grade	8	43.6(11.4)	0.66
Poor Grade	15	51.1(28.4)

* p-values for age, race, gender, and grade are adjusted for smoking

When adjusted for gender and age, carcinomas obtained from smokers harbored significantly more mutations than carcinomas from never smokers.

Relative Risks

	IRR	95% CI	p value
Smoking	1.36	(1.01, 1.84)	0.04
Age	1.30	(0.95, 1.78)	0.11
Gender	1.21	(0.90, 1.64)	0.21

All variables were included in the same model


Conclusions: Pancreatic carcinomas obtained from cigarette smokers harbor significantly more mutations than do carcinomas obtained from never smokers, adjusting for gender and age. The types and patterns of these mutations provide insight into the mechanisms by which cigarette smoking causes pancreatic cancer.
Category: Liver & Pancreas

Wednesday, March 11, 2009 9:30 AM

Poster Session V # 231, Wednesday Morning