Slebos R J, Hoppin J A, Tolbert P E, Holly E A, Brock J W, Zhang R H, Bracci P M, Foley J, Stockton P, McGregor L M, Flake G P, Taylor J A
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Cancer Epidemiol Biomarkers Prev. 2000 Nov;9(11):1223-32.
Pancreatic cancer is a highly fatal cancer with few identified risk factors. Increased risk of pancreatic cancer in tobacco smokers and among diabetic patients is well established, and some reports have suggested associations with coffee consumption and occupational exposure to organochlorines. At present, there is little information regarding the possible association of these risk factors with the known genetic alterations found in pancreatic cancers, such as activation of the K-ras oncogene and inactivation of the p53 tumor suppressor gene. Knowledge of such relationships may help to understand the molecular pathways of pancreatic tumorigenesis. We investigated the association between these molecular defects and risk factors for pancreatic cancer in 61 newly diagnosed patients identified through an ongoing study of pancreatic cancer in the San Francisco Bay Area. Interview information was obtained regarding environmental exposures, medical history, and demographic factors. Serum levels of dichlorodiphenyltrichloroethylene (DDE) and polychlorinated biphenyls were available on a subset of 24 patients. Tumor blocks were located from local hospitals and used for K-ras mutational analysis at codon 12 and for p53 protein immunohistochemistry. The molecular analyses were facilitated through the use of laser capture microdissection, which provides a reliable method to obtain almost pure populations of tumor cells. Mutations in K-ras codon 12 were found in 46 (75%) of 61 pancreatic cancers. A prior diagnosis of diabetes was significantly associated with K-ras negative tumors (P = 0.002, Fisher's exact test). The absence of this mutation was also associated with increased serum levels of DDE, although this association was not statistically significant (P = 0.16, Wilcoxon's test). There was no difference in polychlorinated biphenyl levels between the K-ras wild-type and mutant groups. Immunohistochemical staining for p53 protein did not differ by patient characteristics or clinical history, but significant associations were found with poor glandular differentiation (P = 0.002, chi2 trend test), severe nuclear atypia (P = 0.0007, chi2 trend test), and high tumor grade (P = 0.004, chi2 trend test). Our results are suggestive of the presence of K-ras codon 12 mutation-independent tumorigenesis pathways in patients with prior diabetes and possibly in patients with higher serum levels of DDE. Our results also support a role for the p53 tumor suppressor protein in the maintenance of genomic integrity.
胰腺癌是一种高度致命的癌症，已知的风险因素很少。吸烟者和糖尿病患者患胰腺癌的风险增加已得到充分证实，一些报告表明胰腺癌与咖啡消费以及职业性接触有机氯有关。目前，关于这些风险因素与胰腺癌中已知的基因改变（如K-ras癌基因激活和p53肿瘤抑制基因失活）之间可能存在的关联，几乎没有相关信息。了解此类关系可能有助于理解胰腺肿瘤发生的分子途径。我们在通过旧金山湾区正在进行的一项胰腺癌研究确定的61例新诊断患者中，调查了这些分子缺陷与胰腺癌风险因素之间的关联。获取了有关环境暴露、病史和人口统计学因素的访谈信息。24例患者的子集有血清中滴滴涕（DDE）和多氯联苯的水平数据。从当地医院获取肿瘤组织块，用于K-ras第12密码子的突变分析和p53蛋白免疫组织化学检测。通过使用激光捕获显微切割技术促进了分子分析，该技术提供了一种获得几乎纯肿瘤细胞群体的可靠方法。61例胰腺癌中有46例（75%）发现K-ras第12密码子突变。糖尿病既往诊断与K-ras阴性肿瘤显著相关（P = 0.002，Fisher精确检验）。该突变的缺失也与血清DDE水平升高有关，尽管这种关联无统计学意义（P = 0.16，Wilcoxon检验）。K-ras野生型和突变型组之间多氯联苯水平无差异。p53蛋白免疫组织化学染色在患者特征或临床病史方面无差异，但与腺管分化差（P = 0.002，卡方趋势检验）、严重核异型性（P = 0.0007，卡方趋势检验）和高肿瘤分级（P = 0.004，卡方趋势检验）存在显著关联。我们的结果提示，既往患糖尿病的患者以及可能血清DDE水平较高的患者中存在不依赖K-ras第12密码子突变的肿瘤发生途径。我们的结果还支持p53肿瘤抑制蛋白在维持基因组完整性中的作用。
