Genomic Instability at Both the Base Pair Level and the Chromosomal Level Is Detectable in Earliest PanIN Lesions in Tissues of Chronic Pancreatitis
Genomic Instability at Both the Base Pair Level and the Chromosomal Level Is Detectable in Earliest PanIN Lesions in Tissues of Chronic Pancreatitis
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DOI：
10.1097/mpa.0b013e3181dc62f6
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发表时间：
2010-10-01
期刊：
影响因子：
2.9
通讯作者：
Heinmoeller, Ernst
中科院分区：
文献类型：
--
作者：
Baumgart, Mario;Werther, Meike;Heinmoeller, Ernst
目的：慢性胰腺炎(CP)是胰腺癌(PC)的易感疾病，但其致癌的分子机制尚不明确。方法：对21例CP患者的443例胰腺上皮内瘤变(Panins)、腺泡导管化生(ADM)和正常胰腺导管组织进行杂合性缺失(LOH)和p53、p16、DPC4免疫组织化学检测。用ABI测序技术分析胰腺上皮内肿瘤的p53、p16和Ki-ras基因突变情况。结果：Panin-1和ADM的杂合性丢失率在1.7%(P53)~5.8%(P16)之间。Panin-3中P53蛋白过表达，p16、DPC4蛋白表达缺失。在Panin-1a和ADM中发现p53和p16杂合性突变而不存在LOH，而在Panin-3中发现纯合子突变。从Panin-1a到Panin-3，非整倍体逐渐增加。结论：p5 3、p16基因杂合性突变及染色体不稳定在胰腺癌发生早期即可发生，并呈克隆性扩张，但最终失活主要发生在胰腺癌发生过程中。胰液中非整倍体的检测可能对慢性胰腺炎的早期发现和风险评估有一定的价值。
Objective: Chronic pancreatitis (CP) is a predisposing disease for pancreatic carcinoma (PC), however, precise molecular mechanisms of cancer development in the background of CP are ill defined.Methods: A total of 443 laser-microdissected pancreatic intraepithelial neoplasias (PanINs), acinar-ductal metaplasia (ADM), and normal ducts from 21 patients with CP were analyzed for loss of heterozygosity (LOH) and immunohistochemical protein expression of p53, p16, and DPC4. Pancreatic intraepithelial neoplasias were analyzed for mutations in p53, p16, and Ki-ras genes by ABI sequencing. Aneuploidy was determined by fluorescence in situ hybridization with probes for chromosomes 3, 7, 8, and 17.Results: Loss of heterozygosity rate in PanIN-1 and ADM was between 1.7% (p53) and 5.8% (p16). In PanIN-3, p53 protein overexpression and loss of expression for p16 and DPC4 protein were seen. Heterozygous mutations of p53 and p16 without LOH were found in PanIN-1A and ADM, whereas homozygous mutations were found in PanIN-3. Aneuploidy increased from PanIN-1A to PanIN-3. Ki-ras mutations were discovered first in PanIN-1.Conclusions: Heterozygous mutations of p53-and p16 genes together with chromosomal instability occur early in CP and are clonally expanded, but final inactivation mostly by LOH happens later in pancreatic carcinogenesis. Determination of aneuploidy in pancreatic juice may be of value for early detection and risk assessment in patients with long-standing CP.