Genetic and epigenetic alterations of familial pancreatic cancers.
Genetic and epigenetic alterations of familial pancreatic cancers.
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DOI：
10.1158/1055-9965.epi-08-0630
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Goggins M
中科院分区：
文献类型：
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作者：
Brune K;Hong SM;Li A;Yachida S;Abe T;Griffith M;Yang D;Omura N;Eshleman J;Canto M;Schulick R;Klein AP;Hruban RH;Iacobuzio-Donohue C;Goggins M
对家族性胰腺癌的遗传变化和表观遗传变化知之甚少。本研究的目的是比较散发性和家族性胰腺导管腺癌中常见遗传和表观遗传改变的患病率。从39例家族性胰腺腺癌和36例散发性胰腺腺癌的微解剖癌中分离出DNA。通过BstN1酶切和/或循环测序检测KRAS2突变。在23例家族性胰腺腺癌患者的组织微阵列上，采用免疫组化技术检测TP53和SMAD4的状态，并在选定的病例中采用循环测序技术鉴定TP53基因突变。对一组新鲜冷冻家族性胰腺腺癌患者进行了7个基因（FoxE1、NPTX2、CLDN5、P16、TFPI-2、SPARC、ppENK）的甲基化特异性PCR分析。39例家族性胰腺癌患者中有31例（80%）发现KRAS2突变，36例散发性胰腺癌患者中有28例（78%）发现KRAS2突变。57%的家族性胰腺癌患者观察到p53免疫标记阳性，61%的家族性胰腺癌患者观察到SMAD4标记缺失，这一比例与散发性胰腺癌相似。家族性胰腺癌中异常甲基化的平均发生率为68.4%，与散发性胰腺癌中观察到的异常甲基化发生率无显著差异。家族性胰腺腺癌中KRAS2突变、TP53和SMAD4失活以及7基因组DNA甲基化异常的患病率与散发性胰腺腺癌相似。这些发现支持使用散发性胰腺腺癌标志物来检测家族性胰腺腺癌。
Little is known about the genetic changes and epigenetic changes that contribute to familial pancreatic cancers. The aim of this study was to compare the prevalence of common genetic and epigenetic alterations in sporadic and familial pancreatic ductal adenocarcinomas. DNA was isolated from the microdissected cancers of 39 patients with familial and 36 patients with sporadic pancreatic adenocarcinoma. KRAS2 mutations were detected by BstN1 digestion and/or cycle sequencing. TP53 and SMAD4 status were determined by immunohistochemistry on tissue microarrays of 23 archival familial pancreatic adenocarcinomas and in selected cases by cycle sequencing to identify TP53 gene mutations. Methylation-specific PCR analysis of seven genes (FoxE1, NPTX2, CLDN5, P16, TFPI-2, SPARC, ppENK) was performed on a subset of fresh-frozen familial pancreatic adenocarcinomas. KRAS2 mutations were identified in 31 of 39 (80%) of the familial vs. 28 of 36 (78%) of the sporadic pancreatic cancers. Positive immunolabeling for p53 was observed in 57% of the familial pancreatic cancers and loss of SMAD4 labeling was observed in 61% of the familial pancreatic cancers, rates similar to those observed in sporadic pancreatic cancers. The mean prevalence of aberrant methylation in the familial pancreatic cancers was 68.4%, not significantly different to that observed in sporadic pancreatic cancers. The prevalence of mutant KRAS2, inactivation of TP53 and SMAD4 and aberrant DNA methylation of a 7-gene panel is similar in familial pancreatic adenocarcinomas as in sporadic pancreatic adenocarcinomas. These findings support the use of markers of sporadic pancreatic adenocarcinomas to detect familial pancreatic adenocarcinomas.