E-cadherin germline mutations in familial gastric cancer
E-cadherin germline mutations in familial gastric cancer
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DOI：
10.1038/32918
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发表时间：
1998-03-26
期刊：
影响因子：
64.8
通讯作者：
Reeve, AE
中科院分区：
文献类型：
--
作者：
Guilford, P;Hopkins, J;Reeve, AE
识别易患家族性癌症的基因是了解肿瘤发生分子事件的重要一步，对于受影响家庭的临床管理至关重要。尽管发病率下降，胃癌仍然是全球癌症死亡的主要原因(1)，并且约 10% 的病例显示家族聚集性(2,3)。遗传易感性和环境影响对家族性胃癌的相对影响人们知之甚少，因为人们对易患胃癌的遗传事件知之甚少。在这里，我们描述了在新西兰（Aotearoa）的一个大亲属中鉴定出负责早发、组织学低分化、高级别、弥漫性胃癌(4)的基因，遗传连锁分析表明与钙依赖性细胞粘附蛋白E-钙粘蛋白基因侧翼的标记物有显着的连锁关系。 E-钙粘蛋白基因的测序显示，外显子 7 的供体剪接共有序列中存在 G-->T 核苷酸取代，导致基因产物截短。E-钙粘蛋白表达减少与侵袭性低分化癌相关 (5)。 E-cadherin 表达不足是许多肿瘤类型临床结果不佳的预后标志 (6)，在肿瘤模型中恢复 E-cadherin 表达可以抑制上皮肿瘤细胞的侵袭性 (7,8)。 E-钙粘蛋白在胃癌易感性中的作用通过鉴定其他胃癌家族的失活突变得到证实，在一个家族中，在外显子15中鉴定出移码突变，在第二个家族中，在外显子13中鉴定出提前终止密码子中断。这些结果据我们所知首次描述了家族性胃癌的分子基础，并证实了E-钙粘蛋白突变在癌症中的重要作用。
The identification of genes predisposing to familial cancer is an essential step towards understanding the molecular events underlying tumorigenesis and is critical for the clinical management of affected families. Despite a declining incidence, gastric cancer remains a major cause of cancer death worldwide(1), and about 10% of cases show familial clustering(2,3), The relative contributions of inherited susceptibility and environmental effects to familial gastric cancer are poorly understood because little is known of the genetic events that predispose to gastric cancer. Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer(4) in a large kindred from New Zealand (Aotearoa), Genetic linkage analysis demonstrated significant Linkage to markers flanking the gene for the calcium-dependent cell-adhesion protein E-cadherin. Sequencing of the E-cadherin gene revealed a G-->T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product, Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas(5). Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumour types(6), and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour cells(7,8). The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families, In one family a frameshift mutation,vas identified in exon 15, and in a second family a premature stop codon interrupted exon 13, These results describe, to our knowledge for the first time, a molecular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.