review of literature on clinical pancreatology - The Pancreapedia

carcinogen exposure with cancer risk. The results from these epidemiologic studies wereevaluated and summarized in this <strong>review</strong>. The majority <strong>of</strong> these studies have shown that highintake <strong>of</strong> well-done meat and high exposure to meat carcinogens, particularly HCAs, mayincrease the risk <strong>of</strong> human cancer [338].SmokingCigarette smoking doubles the risk <strong>of</strong> pancreatic cancer, and smoking accounts for 20 to 25percent <strong>of</strong> pancreatic cancers. The recent sequencing <strong>of</strong> the pancreatic cancer genomeprovides an unprecedented opportunity to identify mutational patterns associated withsmoking. It was previously sequenced >750 million bp DNA from 23,219 transcripts in 24adenocarcinomas <strong>of</strong> the pancreas (discovery screen). In this previous study, the 39 genesthat were mutated more than once in the discovery screen were sequenced in an additional90 adenocarcinomas <strong>of</strong> the pancreas (validation screen). Now, it was compared the somaticmutations in the cancers obtained from individuals who ever smoked cigarettes (n=64) to thesomatic mutations in the cancers obtained from individuals who never smoked cigarettes(n=50). When adjusted for age and gender, analyses <strong>of</strong> the discovery screen revealedsignificantly more nonsynonymous mutations in the carcinomas obtained from ever smokers(mean, 53 mutations per tumor) than in the carcinomas obtained from never smokers (mean,38.5). The difference between smokers and nonsmokers was not driven by mutations inknown driver genes in pancreatic cancer (KRAS, TP53, CDKN2A/p16, and SMAD4), butinstead was predominantly observed in genes mutated at lower frequency. No differenceswere observed in mutations in carcinomas from the head versus tail <strong>of</strong> the gland. Pancreaticcarcinomas from cigarette smokers harbor more mutations than do carcinomas from neversmokers [339].A meta-analysis <strong>of</strong> observational studies on association between cigarette smoking andpancreatic cancer was performed to focus, particularly, on the role <strong>of</strong> the studies' quality inaffecting meta-analysis results. A bibliographic search was carried out on PubMed andEMBASE databases until February 15, 2008. Key words were "pancreatic neoplasms,""pancreatic cancer," "smoking," "smoke," "cigarette," "case-control studies," and "cohortstudies." Studies about cigarette smoking and pancreatic cancer were selected andassessed on quality. Six cohort studies and 24 case-control studies were selected, withmedian quality scores <strong>of</strong> 8 (range, 3) and 10 (range, 8), respectively. Pooled case-controlstudies' odds ratio (OR) and cohort studies' risk ratio were, respectively, 1.45 (95 %confidence interval 1.33 to 1.57) and 1.78 (95% CI, 1.64-1.92). After stratifying for qualityscoring, high-quality-scored case-control studies yielded an odds ratio <strong>of</strong> 1.38 (95 %confidence interval 1.27 to 1.49), whereas the others gave an odds ratio <strong>of</strong> 1.52 (95 %confidence interval 1.34 to 1.73). The results <strong>of</strong> meta-analysis for cohort studies showed arisk ratio <strong>of</strong> 1.74 (95 % confidence interval 1.61 to 1.90) and <strong>of</strong> 2.10 (95 % confidenceinterval 1.64 to 2.67), respectively, for high- and low-quality score studies. It was thusconcluded that here is evidence that cigarette smoking is an important risk factor forpancreatic cancer, but the estimate <strong>of</strong> the association greatly relies on the studies' quality[340].To evaluate the effects <strong>of</strong> nicotine and cigarette smoke exposure on mice submitted to 7,12-dimethylbenzanthracene (DMBA) model <strong>of</strong> pancreatic carcinogenesis. One hundred fourteenmale mice were divided into the DMBA-n and DMBA-s groups: the DMBA-n group was given2 mg/kg per dose <strong>of</strong> nicotine subcutaneously for 45 days, and the DMBA-s group wasexposed to 100 mg/m 3 <strong>of</strong> cigarette smoke. At day 16, 1 mg <strong>of</strong> DMBA crystals was implantedin the pancreatic head <strong>of</strong> both groups. Euthanasia was performed in all mice 30 days afterthe surgery. The specimens were evaluated according to the following criteria: normal ducts,reactive hyperplasia, pancreatic intraepithelial neoplasm 3 (PanIN-3), and carcinoma. Thefrequency <strong>of</strong> PanIN in the 3 groups was almost the same when considering the higher-grade