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E-cadherin germline mutations in familial gastric cancer.

机译：家族性胃癌中的E-cadherin种系突变。

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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, and about 10% of cases show familial clustering. 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 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. Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumour types, and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour cells. 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 was 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.
机译：鉴定易患家族性癌症的基因是理解肿瘤发生基础分子事件的必不可少的步骤，对于受影响家庭的临床管理至关重要。尽管发病率下降，但胃癌仍是全世界癌症死亡的主要原因，约有10％的病例显示家族聚集。人们对遗传易感性和环境影响对家族性胃癌的相对贡献知之甚少，因为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）的一个大家庭中，负责早期发作，组织学上分化程度差，高等级，弥漫性胃癌的基因的鉴定。遗传连锁分析表明，与钙依赖性细胞粘附蛋白E-cadherin基因侧翼的标记具有显着连锁关系。 E-钙粘着蛋白基因的测序显示外显子7的供体剪接共有序列中的G→T核苷酸取代，导致基因产物被截短。 E-钙粘着蛋白表达降低与侵袭性，低分化癌相关。 E-钙粘蛋白的低表达是许多肿瘤类型临床预后不良的预后标志物，并且在肿瘤模型中恢复E-钙粘蛋白的表达可以抑制上皮肿瘤细胞的侵袭性。通过鉴定其他胃癌家族中的失活突变，证实了E-钙粘蛋白在胃癌易感性中的作用。在一个家庭中，在第15外显子中发现了移码突变，在第二个家庭中，发现了终止密码子过早终止第13外显子的突变。据我们所知，这些结果首次描述了家族性胃癌的分子基础，并证实了其重要意义。 E-钙粘蛋白突变在癌症中的作用

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