Genetics of adenocarcinomas of the small intestine:: frequent deletions at chromosome 18q and mutations of the SMAD4 gene
Genetics of adenocarcinomas of the small intestine:: frequent deletions at chromosome 18q and mutations of the SMAD4 gene
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DOI：
10.1038/sj.onc.1205041
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发表时间：
2002-01-03
期刊：
影响因子：
8
通讯作者：
Otto, HF
中科院分区：
文献类型：
--
作者：
Bl채ker, H;von Herbay, A;Otto, HF
小肠粘膜约占胃肠道总表面积的90%。然而，腺癌很少发生在这个位置。为了阐明小肠肿瘤发生的遗传学改变，我们研究了17例散发性腺癌。通过比较基因组杂交，在染色体7、8、13 q和20（各5/17）发现染色体材料的经常性增益，而在8 p、17 p（各4/17）和18（8/17例）观察到非随机损失。缺失在5 q，APC肿瘤抑制基因的位置，被认为是在三个案件。染色体臂1 p、5 q、8 p、17 p、18 q、19 p和22 q的微卫星标记分析显示，2例病例的微卫星不稳定表型和18 q21-q22的高频率丢失（80%）。鉴于18 q21-q22缺失的高发生率，我们对SMAD 4进行了测序分析，SMAD 4是TGF β途径的下游组分，位于18 q21。四个肿瘤在高度保守的基因结构域中显示突变，表明TGF β信号传导中断。我们的数据揭示了散发性小肠癌复杂的遗传学改变。然而，大多数肿瘤都有18 q21-q22的缺失，这通常是针对SMAD 4的。这表明TGF β信号传导的中断在小肠肿瘤发生中起关键作用。
The small intestinal mucosa makes up about 90% of the total surface of the gastrointestinal tract. However, adenocarcinomas arise rarely in this location. To elucidate genetic alterations underlying tumour development in the small intestine we investigated 17 sporadic adenocarcinomas. By comparative genomic hybridization recurrent gains of chromosomal material were found at chromosomes 7, 8, 13q, and 20 (5/17, each), while non-random losses were seen at 8p, 17p (4/17, each), and 18 (8/17 cases). Deletions at 5q, the location of the APC tumour suppressor gene, were seen in three cases. Microsatellite analysis with markers on chromosomal arms 1p, 5q, 8p, 17p, 18q, 19p, and 22q revealed a microsatellite instable phenotype in two cases and a high frequency of loss at 18q21-q22 (80%). Given the high incidence of 18q21-q22 deletions, we performed sequencing analysis of SMAD4, a downstream component of the TGF beta -pathway, located at 18q21. Four tumours displayed mutations in highly conserved domains of the gene indicating disruption of TGF beta -signalling. Our data reveal complex genetic alterations in sporadic small intestinal carcinomas. However, most tumours share deletions of 18q21-q22, which frequently target SMAD4. This indicates that disruption of TGF beta -signalling plays a critical role in small intestinal tumorigenesis.