Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome
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DOI：
10.1038/ng0597-64
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发表时间：
1997-05-01
期刊：
影响因子：
30.8
通讯作者：
Parsons, R
中科院分区：
文献类型：
--
作者：
Liaw, D;Marsh, DJ;Parsons, R
Cowden病(CD)是一种常染色体显性遗传癌症易感综合征，与乳腺、甲状腺和皮肤肿瘤的风险增加有关(1-2)。Lhermitte-Duclos病(LDD)是CD家族的一个亚群，与巨头畸形、共济失调和发育不良的小脑节细胞瘤(3-4)有关。这些疾病的共同特征是易患错构瘤，错构瘤是一种良性肿瘤，含有起源组织固有的分化但杂乱无章的细胞。连锁分析已经确定，染色体10q23内的一个单基因座可能导致这两种疾病(5)。该区域内的候选肿瘤抑制基因(PTEN)在散发性脑癌、乳腺癌和前列腺癌中发生突变(6)。另一个小组独立地分离出了同样的基因，称为MMAC1，并在晚期散发性癌症中发现了整个基因的体细胞突变(7)。CD家系中PTEN基因的突变分析已经在5个家系中发现了4个胚系突变，我们发现了无义和错义突变，这些突变被预测破坏了该基因的蛋白酪氨酸/双特异性磷酸酶结构域。因此，PTEN似乎在生殖系中表现为一种肿瘤抑制基因。我们的数据还表明，在发育过程中，PTEN可能在组织器官内不同类型细胞之间的关系中发挥作用。
Cowden disease (CD) is an autosomal dominant cancer predisposition syndrome associated with an elevated risk for tumours of the breast, thyroid and skin(1-2). Lhermitte-Duclos disease (LDD) cosegregates with a subset of CD families and is associated with macrocephaly, ataxia and dysplastic cerebellar gangliocytomatosis(3-4). The common feature of these diseases is a predisposition to hamartomas, benign tumours containing differentiated but disorganized cells indigenous to the tissue of origin. Linkage analysis has determined that a single locus within chromosome 10q23 is likely to be responsible for both of these diseases(5). A candidate tumour suppressor gene (PTEN) within this region is mutated in sporadic brain, breast and prostate cancer(6). Another group has independently isolated the same gene, termed MMAC1, and also found somatic mutations throughout the gene in advanced sporadic cancers(7). Mutational analysis of PTEN in CD kindreds has identified germline mutations in four of five families, We found nonsense and missense mutations that are predicted to disrupt the protein tyrosine/dual-specificity phosphatase domain of this gene. Thus, PTEN appears to behave as a tumour suppressor gene in the germline. Our data also imply that PTEN may play a role in organizing the relationship of different cell types within an organ during development.