Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome
Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome
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DOI：
10.1073/pnas.0802970105
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发表时间：
2008-08-12
影响因子：
11.1
通讯作者：
Malkin, David
中科院分区：
文献类型：
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作者：
Shlien, Adam;Tabori, Uri;Malkin, David
DNA拷贝数变异（CNVs）是人类遗传变异的一个重要而普遍的来源。然而，CNVs对癌症易感性和肿瘤进展的重要性尚未被探讨。Li-Fraumeni综合征（LFS）是一种常染色体显性遗传疾病，其特征是携带种系TP53突变的个体患早发性乳腺癌、肉瘤、脑肿瘤和其他肿瘤的风险显著增加。已知的LFS遗传决定因素并不能完全解释受影响家庭成员的可变临床表型。作为CNVs与癌症更广泛研究的一部分，我们对LFS家族的种系CNVs进行了全基因组分析。在这里，通过使用高密度寡核苷酸阵列检测来自大量健康人群和LFS队列的DNA，我们发现每个基因组的CNVs数量在健康人群中很好地保守，但在这些易患癌症的个体中却惊人地丰富。我们发现，在具有家族癌症史的种系TP53突变携带者中，CNVs显著增加。此外，我们在LFS家族和健康个体中发现了大量已知癌症相关基因与CNVs重合的基因组区域。种系CNVs可能为建立tp53相关肿瘤特征的更显著的染色体变化提供了基础。我们的研究结果表明，筛查易患癌症的CNVs家族可能会发现这些事件异常多的个体。
DNA copy number variations (CNVs) are a significant and ubiquitous source of inherited human genetic variation. However, the importance of CNVs to cancer susceptibility and tumor progression has not yet been explored. Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited disorder characterized by a strikingly increased risk of early-onset breast cancer, sarcomas, brain tumors and other neoplasms in individuals harboring germline TP53 mutations. Known genetic determinants of LFS do not fully explain the variable clinical phenotype in affected family members. As part of a wider study of CNVs and cancer, we conducted a genome-wide profile of germline CNVs in LFS families. Here, by examining DNA from a large healthy population and an LFS cohort using high-density oligonucleotide arrays, we show that the number of CNVs per genome is well conserved in the healthy population, but strikingly enriched in these cancer-prone individuals. We found a highly significant increase in CNVs among carriers of germline TP53 mutations with a familial cancer history. Furthermore, we identified a remarkable number of genomic regions in which known cancer-related genes coincide with CNVs, in both LFS families and healthy individuals. Germline CNVs may provide a foundation that enables the more dramatic chromosomal changes characteristic of TP53-related tumors to be established. Our results suggest that screening families predisposed to cancer for CNVs may identify individuals with an abnormally high number of these events.