Genetic Analysis of Mismatch Repair Genes Alterations in Extramammary Paget Disease
Genetic Analysis of Mismatch Repair Genes Alterations in Extramammary Paget Disease
复制标题
乳房外佩吉特病错配修复基因改变的遗传分析
DOI：
10.1097/pas.0000000000000709
复制
发表时间：
2016-11-01
影响因子：
5.6
通讯作者：
Guan, Ming
中科院分区：
文献类型：
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作者：
Kang, Zhihua;Xu, Feng;Guan, Ming
乳房外佩吉特病（EMPD）是一种罕见的皮肤恶性肿瘤。 EMPD的家族性发生以及EMPD患者继发肿瘤的高风险引起了人们的广泛关注。这些发现强调了遗传改变在这种皮肤癌的肿瘤发生中的重要性。在 EMPD 中进行了错配修复 (MMR) 基因的基因测试和功能分析。结果显示，20例种系MMR基因突变病例中有8例，其中5例表现出微卫星不稳定性（MSI）。免疫组化染色显示，20例患者肿瘤组织中MLH1表达正常，5例患者肿瘤组织中MSH2表达降低。 MSI 和种系突变之间几乎存在显着的相关性。在172例中，种系和体细胞突变率分别为34.3%和13.4%。 MLH1 V384D (15.7%)、R217C (4.1%) 和 I219V (5.2%) 突变在这种癌症中很常见。此外，酵母2-杂交和免疫沉淀测定显示MLH1 V384D和R217C中MLH1和PMS2之间的相互作用减少，但I219V中没有。此外，通过体外 MMR 测定，与野生型和 I219V 突变相比，MLH1 V384D 和 R217C 的 MMR 活性受损。 MMR 基因的种系突变参与了 EMPD 的发病机制，并部分解释了该疾病的遗传异常。
Extramammary Paget disease (EMPD) is a rare cutaneous malignant neoplasm. The familial occurrence of EMPD and the high risk of concomitant secondary tumors in EMPD patients have gained much attention. These findings highlight the importance of genetic alterations in the tumorigenesis of this skin cancer. Genetic tests and functional analysis of mismatch repair (MMR) genes were performed in EMPD. The results showed that 8 of 20 cases with germline MMR genes mutations and 5 of them exhibited microsatellite instability (MSI). Immunohistochemical staining showed that the tumor tissues from 20 patients had the normal expression of MLH1 but 5 cases had the reduced expression of MSH2. There is a nearly significant correlation between MSI and germline mutations. In 172 cases, rates of germline and somatic mutations were 34.3% and 13.4%, respectively. The mutations of MLH1 V384D (15.7%), R217C (4.1%), and I219V (5.2%) were common in this cancer. In addition, the yeast 2-hybrid and immunoprecipitation assays exhibited reduced interaction between MLH1 and PMS2 in MLH1 V384D and R217C but not I219V. Moreover, MLH1 V384D and R217C had impaired MMR activity compared with the wild-type and I219V mutation by an in vitro MMR assay. The germline mutations in MMR genes are involved in the pathogenesis of EMPD and partially explain the genetic abnormalities for this disease.