IDENTIFICATION OF A CHROMOSOME-18Q GENE THAT IS ALTERED IN COLORECTAL CANCERS
IDENTIFICATION OF A CHROMOSOME-18Q GENE THAT IS ALTERED IN COLORECTAL CANCERS
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DOI：
10.1126/science.2294591
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发表时间：
1990-01-05
期刊：
影响因子：
56.9
通讯作者：
VOGELSTEIN, B
中科院分区：
文献类型：
--
作者：
FEARON, ER;CHO, KR;VOGELSTEIN, B
超过 70% 的结直肠癌发生涉及 18q 染色体的等位基因缺失。这种缺失被认为表明受影响区域存在肿瘤抑制基因，但迄今为止，该染色体臂上的候选抑制基因尚未被发现。现在已从疑似位于该基因附近的 18q 染色体区域克隆出一段包含 370 kb 的连续 DNA 片段。 370 kb 区域中的潜在外显子由人类-啮齿动物序列同一性定义，并通过基于聚合酶链式反应的“外显子连接”策略评估潜在外显子的表达。表达的外显子被用作cDNA筛选的探针，以获得编码称为DCC的基因的一部分的克隆；该 cDNA 由 370 kb 基因组区域内的至少 8 个外显子编码。预测的 cDNA 氨基酸序列指定了一种与中性细胞粘附分子和其他相关细胞表面糖蛋白具有序列相似性的蛋白质。虽然 DCC 基因在大多数正常组织（包括结肠粘膜）中表达，但其表达在大多数测试的结直肠癌中大大降低或不表达。在结直肠癌中观察到的 DCC 基因体细胞突变包括基因 5'' 末端的纯合缺失、内含子之一内的点突变，以及紧邻外显子之一下游的 0.17 kb 片段的 10 个 DNA 插入实例。 DCC 基因可能在人类结直肠肿瘤的发病机制中发挥作用，可能是通过改变控制生长的正常细胞间相互作用。
Allelic dletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtained clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neutral cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations with in the DCC gene observed in colorectal cancers included a homozygous deletion of the 5'' end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions with a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.