Information Based Medicine Program, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, 2305, Australia.
CSIRO Preventative Health Flagship and Division of Animal, Food and Health Sciences, North Ryde, New South Wales, 2113, Australia.
Genes (Basel). 2013 Sep 26;4(4):536-55. doi: 10.3390/genes4040536.
Hereditary non-polyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer (CRC) predisposition and by definition describes families which conform to the Amsterdam Criteria or reiterations thereof. In ~50% of patients adhering to the Amsterdam criteria germline variants are identified in one of four DNA Mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Loss of function of any one of these genes results in a failure to repair DNA errors occurring during replication which can be most easily observed as DNA microsatellite instability (MSI)-a hallmark feature of this disease. The remaining 50% of patients without a genetic diagnosis of disease may harbour more cryptic changes within or adjacent to MLH1, MSH2, MSH6 or PMS2 or elsewhere in the genome. We used a high density cytogenetic array to screen for deletions or duplications in a series of patients, all of whom adhered to the Amsterdam/Bethesda criteria, to determine if genomic re-arrangements could account for a proportion of patients that had been shown not to harbour causative mutations as assessed by standard diagnostic techniques. The study has revealed some associations between copy number variants (CNVs) and HNPCC mutation negative cases and further highlights difficulties associated with CNV analysis.
遗传性非息肉病性结直肠癌（HNPCC）是最常见的遗传性结直肠癌（CRC）易感性形式，根据定义，它描述了符合阿姆斯特丹标准或其重复标准的家族。在符合阿姆斯特丹标准的~50%的患者中，在四个 DNA 错配修复（MMR）基因 MLH1、MSH2、MSH6 和 PMS2 中的一个中鉴定出种系变异。这些基因中的任何一个的功能丧失都会导致复制过程中发生的 DNA 错误无法修复，这最容易观察到作为这种疾病的标志特征的 DNA 微卫星不稳定性（MSI）。没有遗传疾病诊断的其余 50%的患者可能在 MLH1、MSH2、MSH6 或 PMS2 内或附近或基因组的其他部位存在更多隐匿性变化。我们使用高密度细胞遗传学阵列筛选一系列符合阿姆斯特丹/贝塞斯达标准的患者中的缺失或重复，以确定基因组重排是否可以解释一部分已被证明不携带致病突变的患者，这些患者通过标准诊断技术评估。该研究揭示了拷贝数变异（CNV）与 HNPCC 突变阴性病例之间的一些关联，并进一步强调了 CNV 分析相关的困难。
