Medical Department, Campus Innenstadt, Klinikum der Universität, Munich, Germany; MGZ-Center of Medical Genetics, Munich, Germany.
J Med Genet. 2011 Aug;48(8):513-9. doi: 10.1136/jmedgenet-2011-100050. Epub 2011 Jun 28.
A positive family history, germline mutations in DNA mismatch repair genes, tumours with high microsatellite instability, and loss of mismatch repair protein expression are the hallmarks of hereditary non-polyposis colorectal cancer (Lynch syndrome). However, in ~10-15% of cases of suspected Lynch syndrome, no disease-causing mechanism can be detected.
Oligo array analysis was performed to search for genomic imbalances in patients with suspected mutation-negative Lynch syndrome with MLH1 deficiency in their colorectal tumours.
A deletion in the LRRFIP2 (leucine-rich repeat flightless-interacting protein 2) gene flanking the MLH1 gene was detected, which turned out to be a paracentric inversion on chromosome 3p22.2 creating two new stable fusion transcripts between MLH1 and LRRFIP2. A single-nucleotide polymorphism in MLH1 exon 8 was expressed from both alleles, initially pointing to appropriate MLH1 function at least in peripheral cells. In a second case, an inherited duplication of the MLH1 gene region resulted in constitutional MLH1 promoter methylation. Constitutional MLH1 promoter methylation may therefore in rare cases be a heritable disease mechanism and should not be overlooked in seemingly sporadic patients.
阳性家族史、DNA 错配修复基因种系突变、具有高微卫星不稳定性的肿瘤以及错配修复蛋白表达缺失是遗传性非息肉病性结直肠癌（林奇综合征）的特征。然而，在约 10-15%疑似林奇综合征病例中，无法检测到致病机制。
对结直肠肿瘤中 MLH1 缺乏的疑似突变阴性林奇综合征患者进行寡核苷酸阵列分析，以寻找基因组失衡。
检测到 MLH1 基因侧翼的 LRRFIP2（富含亮氨酸的无翅型飞行蛋白 2）基因缺失，这实际上是 3p22.2 号染色体上的臂间倒位，导致 MLH1 和 LRRFIP2 之间产生两个新的稳定融合转录本。MLH1 外显子 8 中的单核苷酸多态性从两个等位基因表达，最初表明至少在外周细胞中 MLH1 功能适当。在第二个病例中，MLH1 基因区域的遗传性重复导致了组成性 MLH1 启动子甲基化。因此，在罕见情况下，组成性 MLH1 启动子甲基化可能是一种遗传性疾病机制，在看似散发性患者中不应忽视。
