Isolated loss of PMS2 expression in colorectal cancers: Frequency, patient age, and familial aggregation
Isolated loss of PMS2 expression in colorectal cancers: Frequency, patient age, and familial aggregation
复制标题
DOI：
10.1158/1078-0432.ccr-05-0661
复制
发表时间：
2005-09-15
影响因子：
11.5
通讯作者：
Thibodeau, SN
中科院分区：
文献类型：
--
作者：
Gill, S;Lindor, NM;Thibodeau, SN
目的：大多数具有高水平微卫星不稳定性(MSI-H)的结直肠癌表现出参与DNA错配修复过程的蛋白的免疫组织化学表达缺失，最常见的涉及MLH1和MSH2。不太常见的是，第三种DNA错配修复蛋白MSH6也可能作为主要事件丢失。患有MSI-H的肿瘤很少表现出这三种蛋白的正常表达，这种情况下导致MSI-H表型的遗传缺陷尚不清楚。PMS2是DNA错配修复复合体的另一个成员。在有MLH1表达缺失的肿瘤中，它的表达通常是缺失的。我们试图描述PMS2选择性表达缺失的频率和临床相关性与MSI-H肿瘤表型。实验设计：来自临床和研究证实的2,719例结直肠癌进行研究。进行肿瘤MSI检测和MLH1、MSH2、MSH6、PMS2的免疫组织化学染色。结果：在2,719个肿瘤中，535个肿瘤为微卫星H。其中，93%表现为MLH1、MSH2和/或MSH6的表达缺失。38例显示这些蛋白表达正常。38例肿瘤中32例PMS2免疫组织化学染色阳性。结论：97%的MSI-H肿瘤中，97%的MSI-H肿瘤表现出这四种错配修复蛋白中的一种或多种表达缺失。在具有MSI-.h表型的结直肠癌中，72%的病例存在PMS2的选择性缺失，但MLH1、MSH2和MSH6的表达没有变化。潜在的机制无法从这项研究中确定，但可能涉及其他DNA错配修复的点突变、免疫组织化学表达保留的基因、PMS2的体细胞失活；或PMS2的胚系突变。
Purpose: Most colorectal cancers that have high level's of microsatellite instability (MSI-H) show loss of immunohistochemical expression of proteins that participate in the DNA mismatch repair process, most often involving MLH1 and MSH2. Less commonly, a third DNA mismatch repair protein, MSH6, may also be lost as the primary event. Rarely, tumors with MSI-H show normal expression of these three proteins.The genetic deficiency leading to the MSI-H phenotype in such Cases is unknown. PMS2 is another member of the DNA mismatch repair complex. Its expression is generally lost in tumors with MLH1 loss, of expression.: Rarely, there is selective loss of PMS2 expression. We sought to describe the frequency and clinical correlates of selective loss of expression of PMS2 with the MSI-H tumor phenotype.Experimental Design: Two thousand seven hundred nineteen colorectal cancers from both Clinic- and research-based ascertainment were studied. Tumor MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 were conducted. Medical records were abstracted for age at diagnosis, gender, colorectal cancer site, and family history.Results: Five hundred thirty-five of the 2,719 tumors were MSI-H. Of these, 93% showed loss of expression of MLH1, MSH2, and/or MSH6. Thirty-eight showed normal expression for these proteins. PMS2 immunohistochemical staining was successful in 32 of 38 of these tumors. Of,the 32; selective loss of expression of,PMS2..,This Was,associated with young aged of diagnosis and right-sided location but not with, a striking family history of cancer.Conclusions: Overall, 97% of the MSI-H tumors showed loss of expression for one or more of these four mismatch repair proteins. Selective-loss of expression of PMS2 was present in 72% of cases in which colorectal cancers had an MSI-.H phenotype but no alteration of expression of MLH1, MSH2, and MSH6. The underlying mechanism involved Cannot be determined from this study but could involve point mutations in other DNA mismatch repair, genes with retention of immunohistochemical expression, somatic inactivation of PMS2; or germ line mutation of PMS2.