Genotype-phenotype correlation in MMR mutation-positive families with Lynch syndrome
Genotype-phenotype correlation in MMR mutation-positive families with Lynch syndrome
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DOI：
10.1007/s00384-013-1685-x
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发表时间：
2013-09-01
影响因子：
2.8
通讯作者：
Duran, Mercedes
中科院分区：
文献类型：
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作者：
Perez-Cabornero, Lucia;Infante, Mar;Duran, Mercedes
背景遗传性非息肉病性结直肠癌(HNPCC)是由错配修复(MMR)基因杂合突变引起的。大约85%的遗传性HNPCC患者在MLH1和MSH2有胚系突变。HNPCC患者患结肠癌的风险增加。起病年龄较早，主要是右侧结肠癌，以及同步和异时性癌症是该综合征的其他特征。HNPCC表现出不同的临床表型，在一些国家观察到基因突变频率的差异。方法在符合纳入标准的264个家系中，鉴定出MLH1、MSH2或MSH6基因发生恶性突变的家系共46人。我们评估这些临床病理特征与不同的遗传参数(基因突变、突变类型或高危家系中MMR系统的改变)之间的关系，以建立表型与我们系列中的基因之间的关系。结果疾病的表型似乎不受突变类型的影响，而是受突变基因的影响。多发性肿瘤的存在与MSH2基因的突变有关。在MLH1和MSH2突变的家系中，首次诊断结直肠癌(CRC)的平均年龄几乎相同，约50岁，但对于MSH6突变携带者，这一年龄可能增加近10岁。结论确定基因型与表型的相关性可以提供更具体的监测方案，重点关注个体风险。
Background Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by heterozygous mutations in mismatch repair (MMR) genes. Approximately 85 % of genetically defined HNPCC patients have germline mutations in MLH1 and MSH2. HNPCC patients are at increased risk of developing extracolonic cancers. The early age of onset, predominantly right-sided colon cancers, and synchronous and metachronous cancers are other features of the syndrome. HNPCC shows heterogeneous clinical phenotypes, and differences in gene mutation frequencies have been observed in some countries. Several investigators have tried to correlate the phenotype with the affected gene.Methods A total of 46 individuals from 22 unrelated families, of the 264 families fulfilling the inclusion criteria, with deleterious mutations in MLH1, MSH2, or MSH6 genes were identified. We evaluated these clinicopathological features in their relation to different genetic parameters (gene mutated, type of mutation, or alteration of the MMR systemin high-risk families) in order to establish a relationship between the phenotype and the genotype in our series.Results The phenotype of the disease seems not to be influenced by the type of mutation, but rather by the mutated gene. The presence of multiple tumors is associated with mutations in the MSH2 gene. The mean age at diagnosis of the first colorectal cancer (CRC) was almost identical in families with mutations in MLH1 and MSH2, about 50 years of age, but this age may increase by almost 10 years for MSH6 mutation carriers.Conclusion The identification of genotype-phenotype correlations could provide a more specific surveillance program focused on the individualized risk.