A new germline stop codon mutation in exon 15 of the APC gene predisposing to familial adenomatous polyposis
A new germline stop codon mutation in exon 15 of the APC gene predisposing to familial adenomatous polyposis
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DOI：
10.5301/jbm.5000042
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发表时间：
2013-10-01
影响因子：
2
通讯作者：
Greco, Marilena
中科院分区：
文献类型：
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作者：
Schirosi, Laura;Pellegrino, Marcello;Greco, Marilena
家族性腺瘤性息肉病（FAP）是一种常染色体显性遗传病，与大肠腺瘤性息肉病（APC）基因的种系突变有关。它的特点是发现许多腺瘤性息肉，如果不治疗，就会发展成结直肠癌。我们研究了一个有FAP病史的意大利家庭和先证者的相关结直肠肿瘤样本。血液样本的测序分析显示，APC基因（外显子15）存在从未报道过的种系突变：位置c. 2126的杂合G缺失导致过早停止密码子（p.Gly721GlufsX6）和截断蛋白。在结直肠肿瘤组织中也发现了这种突变，以及第二种已知的致病性杂合子体细胞突变c.4348C>T (p.a g1450x)，该突变产生过早截断的蛋白质。因此，新发现的种系突变与FAP有关，根据Knudson的“两击”假说，可以认为是这些患者中导致结直肠癌发病的第一个事件。使APC基因第二等位基因失活的体细胞撞击位于该基因的突变簇区；这不是一个随机事件，因为它取决于种系突变的位置。APC的失活对细胞产生肿瘤生长优势。
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder related to germline mutations of the adenomatous polyposis coli (APC) gene. It is characterized by the detection of numerous adenomatous polyps that, if untreated, develop into colorectal cancer. We studied an Italian family with FAP history and the related colorectal tumor sample of the proband. Sequencing analysis of blood samples revealed the presence of a never-reported germline mutation in the APC gene (exon 15): an heterozygous G deletion at position c. 2126 resulting in a premature stop codon (p.Gly721GlufsX6) and in a truncated protein. This mutation was also identified in the colorectal tumor tissue, together with a second known pathogenic heterozygotic somatic mutation, c.4348C>T (p.Arg1450X), which generates a premature truncated protein. The novel identified germline mutation is therefore related to FAP and, in accordance with Knudson's "two hit" hypothesis, can be considered the first event predisposing to the insurgence of colorectal cancer in these patients. The somatic hit inactivating the second allele of the APC gene is located in the mutation cluster region of the gene; this is not a random event since it depends on the position of the germline mutation. The inactivation of APC generates the neoplastic growth advantage to the cell.