Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Hum Mutat. 2010 Mar;31(3):317-24. doi: 10.1002/humu.21190.
Most hereditary nonpolyposis colorectal cancer (HNPCC) patients inherit a defective allele of a mismatch repair (MMR) gene, usually MLH1 or MSH2, resulting in high levels of microsatellite instability (MSI-H) in the tumors. Presence of MSI in the normal tissues of mutation carriers has been controversial. Here we directly compare MSI in the peripheral blood leukocyte (PBL) DNA of seven HNPCC patients carrying different types of pathogenic MMR mutations in MLH1 and MSH2 genes with the PBL DNA of normal age-matched controls and of patients with sporadic colorectal cancer (SCRC). Small pool PCR (SP-PCR) was used studying three microsatellite loci for at least 100 alleles each in most samples. The average frequencies of mutant microsatellite fragments in each HNPCC patient (0.04-0.24) were significantly higher (p<0.01) relative to their age-matched normal controls with mutant frequencies (MF) from 0.00 to 0.06, or SCRC patients (MF from 0.01-0.03). The data support the conclusions that higher MF in the PBL DNA of HNPCC patients is real and reproducible, may vary in extent according to the type of germline MMR mutation and the age of the individual, and provide a possible genetic explanation for anticipation in HNPCC families.
大多数遗传性非息肉病性结直肠癌（HNPCC）患者遗传了错配修复（MMR）基因的缺陷等位基因，通常是 MLH1 或 MSH2，导致肿瘤中微卫星不稳定性（MSI-H）水平升高。突变携带者正常组织中存在 MSI 一直存在争议。在这里，我们直接比较了携带 MLH1 和 MSH2 基因中不同类型致病性 MMR 突变的 7 名 HNPCC 患者的外周血白细胞（PBL）DNA 中的 MSI 与正常年龄匹配对照者和散发性结直肠癌（SCRC）患者的 PBL DNA。使用小池 PCR（SP-PCR）研究了三个微卫星位点，大多数样本的每个位点至少研究了 100 个等位基因。每个 HNPCC 患者的突变微卫星片段的平均频率（0.04-0.24）明显高于（p<0.01）与其年龄匹配的正常对照者（突变频率（MF）为 0.00 至 0.06），或 SCRC 患者（MF 为 0.01-0.03）。这些数据支持以下结论：HNPCC 患者 PBL DNA 中更高的 MF 是真实且可重复的，可能根据种系 MMR 突变的类型和个体的年龄而有所不同，并为 HNPCC 家族中的预期现象提供了可能的遗传解释。
