Gene conversion is a frequent mechanism of inactivation of the wild-type allele in cancers from MLH1/MSH2 deletion carriers
Gene conversion is a frequent mechanism of inactivation of the wild-type allele in cancers from MLH1/MSH2 deletion carriers
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DOI：
10.1158/0008-5472.can-05-4043
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发表时间：
2006-01-15
期刊：
影响因子：
11.2
通讯作者：
Heinimann, K
中科院分区：
文献类型：
--
作者：
Zhang, J;Lindroos, A;Heinimann, K
遗传性非息肉病性结直肠癌（HNPCC）是一种常染色体显性遗传的癌症易感综合征，由DNA错配修复基因（主要是MLH 1和MSH 2）的种系突变引起，其中大的基因组重排占所有突变的5%至20%。虽然对理解癌症的发生至关重要，但对HNPCC肿瘤发生中的第二个体细胞打击（通常称为杂合性丢失）知之甚少。在这里，我们采用了最近开发的方法，多重连接依赖探针扩增，研究MLH 1/MSH 2拷贝数的变化在16个无关的瑞士HNPCC患者，其癌症显示微卫星不稳定性和MLH 1或MSH 2表达的损失，但在其中没有生殖系突变可以检测到常规筛选。本研究的目的是（a）确定瑞士MLH 1/MSH 2突变携带者中大基因组重排的比例，（B）研究MLH 1/MSH 2生殖系缺失携带者肿瘤中杂合性缺失作为第二个体细胞事件的频率和性质。发现大的基因组缺失分别占MLH 1和MSH 2突变的4.3%和10.7%。多重连接依赖的探针扩增分析18个癌症标本从两个独立的瑞士和芬兰MLH 1/MSH 2缺失载体显示，体细胞突变相同的生殖细胞系中经常发生在结直肠癌（6 11; 55%），也存在于结肠外HNTCC相关肿瘤。染色体特异性标记分析暗示野生型等位基因的丢失主要通过基因座限制性重组事件发生，即，基因转换，而不是相应基因座的有丝分裂重组或缺失。
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited cancer predisposition syndrome caused by germ line mutations in DNA mismatch repair genes, predominantly MLH1 and MSH2, with large genomic rearrangements accounting for 5% to 20% of all mutations. Although crucial to the understanding of cancer initiation, little is known about the second, somatic hit in HNPCC tumorigenesis, commonly referred to as loss of heterozygosity. Here, we applied a recently developed method, multiplex ligation-dependent probe amplification, to study MLH1/MSH2 copy number changes in 16 unrelated Swiss HNPCC patients, whose cancers displayed microsatellite instability and loss of MLH1 or MSH2 expression, but in whom no germ line mutation could be detected by conventional screening. The aims of the study were (a) to determine the proportion of large genomic rearrangements among Swiss MLH1/MSH2 mutation carriers and (b) to investigate the frequency and nature of loss of heterozygosity as a second, somatic event, in tumors from MLH1/MSH2 germ line deletion carriers. Large genomic deletions were found to account for 4.3% and 10.7% of MLH1 and MSH2 mutations, respectively. Multiplex ligation-dependent probe amplification analysis of 18 cancer specimens from two independent sets of Swiss and Finnish MLH1/MSH2 deletion carriers revealed that somatic mutations identical to the ones in the germ line occur frequently in colorectal cancers (6 of 11; 55%) and are also present in extracolonic HNTCC-associated tumors. Chromosome-specific marker analysis implies that loss of the wild-type allele predominantly occurs through locus-restricted recombinational events, i.e., gene conversion, rather than mitotic recombination or deletion of the respective gene locus.