Walch A, Bink K, Hutzler P, Zitzelsberger H, Braselmann H, Aubele M, Höfler H, Werner M
Technische Universität München, Institute of Pathology, Munich, Germany.
Verh Dtsch Ges Pathol. 2001;85:257-63.
Information about numerical genomic alterations in the tumorigenesis of Barrett's adenocarcinoma (BCA) is still limited. In order to search for gene amplification and ploidy status, a series of locus-specific DNA probes and associated centromere probes was analysed in the metaplasia-dysplasia-adenocarcinoma-sequence.
Fluorescence in situ hybridisation (FISH) was performed on paraffin sections with locus-specific DNA probes for D7S486, c-myc, cyclin D1, Her-2/neu, 20q13.2 and associated chromosomes 7, 8, 11, 17 and 20. Corresponding areas of intestinal metaplasia (IM, n = 5), low grade dysplasia (LGD, n = 9), high grade dysplasia (HGD, n = 15) and BCA (n = 16) were analysed.
Gene amplification of c-myc, Cyclin D1, Her-2/neu and 20q13.2 was observed in 15-35% of BCA. Coincident amplification of genes was also present. Polysomies for all investigated centromere probes were highly prevalent (up to 85%). Gene amplification was also demonstrated in HGD lesions. Polysomies were observed in HGD in high frequency (up to 80%). Extensive genetic heterogeneity was observed in both, BCA and HGD displaying different levels of amplification. None of the samples with LGD showed a locus-specific amplification, but polysomies for all investigated chromosomes were present in 18-48% of LGD. No changes were detected in BCA associated IM and squamous epithelium.
Our data indicate that oncogene amplification of c-myc, cyclin D1, Her-2/neu, and 20q13.2 occurring in BCA and less frequently in HGD is a late event in the tumorigenesis. Polysomies of chromosomes 7, 8, 11, 17 and 20, which were highly prevalent in BCA and HGD occur already at the stage of LGD. This may be a result of an early polyploidization, preceding the later genetic events, such as gene amplification in HGD and BCA. The detection of shared numerical genomic changes and the detected extensive genetic heterogeneity in the metaplasia-dysplasia-carcinoma-sequence in Barrett's esophagus supports the hypothesis of a process of multiclonal expansion underlying this progression.
关于巴雷特腺癌（BCA）肿瘤发生过程中基因组数字改变的信息仍然有限。为了探寻基因扩增和倍性状态，在化生-发育异常-腺癌序列中分析了一系列位点特异性DNA探针及相关着丝粒探针。
使用针对D7S486、c-myc、细胞周期蛋白D1、Her-2/neu、20q13.2的位点特异性DNA探针以及相关的7号、8号、11号、17号和20号染色体，对石蜡切片进行荧光原位杂交（FISH）。分析了肠化生（IM，n = 5）、低级别发育异常（LGD，n = 9）、高级别发育异常（HGD，n = 15）和BCA（n = 16）的相应区域。
在15%-35%的BCA中观察到c-myc、细胞周期蛋白D1、Her-2/neu和20q13.2的基因扩增。基因同时扩增的情况也存在。所有研究的着丝粒探针的多体性都非常普遍（高达85%）。在HGD病变中也证实了基因扩增。在HGD中多体性的观察频率很高（高达80%）。在BCA和HGD中均观察到广泛的遗传异质性，显示出不同程度的扩增。LGD样本均未显示位点特异性扩增，但在18%-48%的LGD中存在所有研究染色体的多体性。在与BCA相关的IM和鳞状上皮中未检测到变化。
我们的数据表明，BCA中发生的c-myc、细胞周期蛋白D1、Her-2/neu和20q13.2的致癌基因扩增在HGD中较少见，是肿瘤发生过程中的晚期事件。7号、8号、11号、17号和20号染色体的多体性在BCA和HGD中非常普遍，在LGD阶段就已出现。这可能是早期多倍体化的结果，早于后期的遗传事件，如HGD和BCA中的基因扩增。在巴雷特食管化生-发育异常-癌序列中检测到的共享基因组数字变化以及广泛的遗传异质性支持了这一进展背后多克隆扩增过程的假设。
