Genetic mutations associated with cigarette smoking in pancreatic cancer.
Genetic mutations associated with cigarette smoking in pancreatic cancer.
复制标题
DOI：
10.1158/0008-5472.can-09-0015
复制
发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Hruban RH
中科院分区：
文献类型：
--
作者：
Blackford A;Parmigiani G;Kensler TW;Wolfgang C;Jones S;Zhang X;Parsons DW;Lin JC;Leary RJ;Eshleman JR;Goggins M;Jaffee EM;Iacobuzio-Donahue CA;Maitra A;Klein A;Cameron JL;Olino K;Schulick R;Winter J;Vogelstein B;Velculescu VE;Kinzler KW;Hruban RH
吸烟使胰腺癌的风险增加一倍，吸烟占胰腺癌的20%至25%。最近对胰腺癌基因组的测序为识别与吸烟相关的突变模式提供了前所未有的机会。我们先前对来自24种胰腺腺癌中的23，219种转录物的超过7.5亿个碱基对的DNA进行了测序（“发现筛选”）。在这项先前的研究中，在发现筛选中突变超过一次的39个基因在另外90个胰腺腺癌中被测序（“验证筛选”）。在这里，我们比较了从曾经吸烟的个体（n=64）获得的癌症中的体细胞突变与从从不吸烟的个体（n=50）获得的癌症中的体细胞突变。当调整年龄和性别时，发现筛选的分析显示，从曾经吸烟者获得的癌中的非同义突变（平均每个肿瘤53.1个突变，SD 27.9）显著多于从不吸烟者获得的癌（平均38.5，SD 11.1，p=0.04）。吸烟者和非吸烟者之间的差异不是由胰腺癌中已知驱动基因（KRAS，TP 53，p16/CDKN 2A和SMAD 4）的突变驱动的，而是主要在较低频率突变的基因中观察到的。在腺体头部与尾部的癌中未观察到突变差异。吸烟者的胰腺癌比从不吸烟者的癌症含有更多的突变。这些突变的类型和模式提供了深入了解吸烟导致胰腺癌的机制。
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 over 750 million base pairs of 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 non-synonymous 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 non-smokers was not driven by mutations in known driver genes in pancreatic cancer (KRAS, TP53, p16/CDKN2A and SMAD4), but instead was predominantly observed in genes mutated at lower frequency. No differences were observed in mutations in carcinomas from the head vs. 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.