Castillejo Adela, Hernández-Illán Eva, Rodriguez-Soler María, Pérez-Carbonell Lucía, Egoavil Cecilia, Barberá Victor M, Castillejo María-Isabel, Guarinos Carla, Martínez-de-Dueñas Eduardo, Juan María-Jose, Sánchez-Heras Ana-Beatriz, García-Casado Zaida, Ruiz-Ponte Clara, Brea-Fernández Alejandro, Juárez Miriam, Bujanda Luis, Clofent Juan, Llor Xavier, Andreu Montserrat, Castells Antoni, Carracedo Angel, Alenda Cristina, Payá Artemio, Jover Rodrigo, Soto José-Luis
Molecular Genetics Laboratory, Elche University Hospital, Elche, Spain.
Research Laboratory, Alicante University Hospital, Alicante, Spain.
J Med Genet. 2015 Jul;52(7):498-502. doi: 10.1136/jmedgenet-2015-103076. Epub 2015 Apr 23.
The prevalence of MLH1 constitutional epimutations in the general population is unknown. We sought to analyse the prevalence of MLH1 constitutional epimutations in unselected and selected series of patients with colorectal cancer (CRC).
Patients with diagnoses of CRC (n=2123) were included in the unselected group. For comparison, a group of 847 selected patients with CRC who fulfilled the revised Bethesda guidelines (rBG) were also included. Somatic and constitutional MLH1 methylation was assayed via methylation-specific multiplex ligation-dependent probe amplification of cases lacking MLH1 expression. Germline alterations in mismatch-repair (MMR) genes were assessed via Sanger sequencing and methylation-specific multiplex ligation-dependent probe amplification.
Loss of MLH1 expression occurred in 5.5% of the unselected series and 12.5% of the selected series (p<0.0001). No constitutional epimutations in MLH1 were detected in the unselected population (0/62); five cases from the selected series were positive for MLH1 epimutations (15.6%, 5/32; p=0.004).
Our results suggest a negligible prevalence of MLH1 constitutional epimutations in unselected cases of CRC. Therefore, MLH1 constitutional epimutation analysis should be conducted only for patients who fulfil the rBG and who lack MLH1 expression with methylated MLH1.
一般人群中MLH1基因组成型表位突变的患病率尚不清楚。我们试图分析未经选择和经过选择的一系列结直肠癌（CRC）患者中MLH1基因组成型表位突变的患病率。
未经选择的组纳入了诊断为CRC的患者（n = 2123）。为了进行比较，还纳入了一组847例符合修订的贝塞斯达指南（rBG）的经过选择的CRC患者。通过对缺乏MLH1表达的病例进行甲基化特异性多重连接依赖性探针扩增来检测体细胞和基因组成型MLH1甲基化。通过桑格测序和甲基化特异性多重连接依赖性探针扩增评估错配修复（MMR）基因中的种系改变。
在未经选择的系列中，5.5%的患者出现MLH1表达缺失，在经过选择的系列中这一比例为12.5%（P<0.0001）。在未经选择的人群中未检测到MLH1的基因组成型表位突变（0/62）；经过选择的系列中有5例MLH1表位突变呈阳性（15.6%，5/32；P = （此处原文有误，应为p）0.004）。
我们的结果表明，在未经选择的CRC病例中，MLH1基因组成型表位突变的患病率可忽略不计。因此，仅应对符合rBG且MLH1表达缺失且MLH1甲基化的患者进行MLH1基因组成型表位突变分析。
