Breakpoint determination of 15 large deletions in Peutz-Jeghers subjects
Breakpoint determination of 15 large deletions in Peutz-Jeghers subjects
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DOI：
10.1007/s00439-010-0859-7
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发表时间：
2010-10-01
期刊：
影响因子：
5.3
通讯作者：
Ciccone, Roberto
中科院分区：
文献类型：
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作者：
Resta, Nicoletta;Giorda, Roberto;Ciccone, Roberto
Peutz-Jeghers综合征（PJS）是一种常染色体显性息肉病，伴有多种癌症的风险增加。STK11/LKB1（以下简称STK11）种系突变占PJS病例的绝大多数，而大缺失约占30%。我们在此报告了51例临床特征明确的PJS患者队列中发现的15个大缺失的首次彻底分子表征。通过MLPA分析对缺失进行鉴定，并通过定制CGH-array和定量PCR对其进行鉴定以确定其边界。在6例患者中，缺失范围从2.9 kb到180 kb不等，移除了一个或多个与STK11基因相邻的位点，而在其余9例患者中存在部分STK11基因缺失。通过DNA测序，我们能够精确地描述每种情况下的断点。在30个断点中，16个位于Alu元件，揭示了非等位基因同源重组（non-allelic homologous recombination， NAHR）可能是STK11基因缺失的机制，该基因位于Alu密度高的区域。在其他情况下，其他机制可以假设，如微同源介导的末端连接（MMEJ）或非同源末端连接（NHEJ）。总之，我们在这里证明了与PJS相关的大缺失的非随机发生。我们所有的患者都有典型的PJS表型，这表明SBNO2、C19orf26、ATP5D、MIDN、C19orf23、CIRBP、C19orf24和EFNA2的单倍性不足对他们的临床表型没有明显影响。
The Peutz-Jeghers Syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers. STK11/LKB1 (hereafter named STK11) germline mutations account for the large majority of PJS cases whereas large deletions account for about 30% of the cases. We report here the first thorough molecular characterization of 15 large deletions identified in a cohort of 51 clinically well-characterized PJS patients. The deletions were identified by MLPA analysis and characterized by custom CGH-array and quantitative PCR to define their boundaries. The deletions, ranging from 2.9 to 180 kb, removed one or more loci contiguous to the STK11 gene in six patients, while partial STK11 gene deletions were present in the remaining nine cases. By means of DNA sequencing, we were able to precisely characterize the breakpoints in each case. Of the 30 breakpoints, 16 were located in Alu elements, revealing non-allelic homologous recombination (NAHR) as the putative mechanism for the deletions of the STK11 gene, which lays in a region with high Alu density. In the remaining cases, other mechanisms could be hypothesized, such as microhomology-mediated end-joining (MMEJ) or non-homologous end-joining (NHEJ). In conclusion we here demonstrated the non-random occurrence of large deletions associated with PJS. All our patients had a classical PJS phenotype, which shows that haploinsufficiency for SBNO2, C19orf26, ATP5D, MIDN, C19orf23, CIRBP, C19orf24,and EFNA2, does not apparently affect their clinical phenotype.