Department of Pathology and Oncobiology, Montpellier University Hospital, Montpellier, France.
IRCM Inserm, Montpellier University, Montpellier, France.
Hum Mutat. 2019 Jun;40(6):716-720. doi: 10.1002/humu.23725.
Lynch syndrome (LS) is the most frequent cause of hereditary colorectal cancer. A subset of patients with a history of LS shows no causal germline pathogenic alteration and are identified as having Lynch-like syndrome (LLS). Alu retrotransposons are the most abundant mobile DNA sequences in the human genome and have been associated with numerous human cancers by either disrupting coding regions or altering epigenetic modifications or splicing signals. We report a family first classified as having LLS by Sanger sequencing analysis. Next-generation sequencing (NGS) analysis identified an AluY5a insertion in MLH1 exon 6 that led to exon skipping. This splicing alteration inducing a pathogenic frameshift was found in patients who developed colorectal adenocarcinomas. Retroelement insertion might thus be an important but underestimated mechanism of cancer genetics that could be systematically tested in patients with a phenotype suggesting LS to accurately assess family risk and surveillance approaches.
林奇综合征（LS）是遗传性结直肠癌最常见的病因。有 LS 病史的一部分患者没有因果性种系致病性改变，被确定为具有林奇样综合征（LLS）。Alu 反转录转座子是人类基因组中最丰富的移动 DNA 序列，通过破坏编码区域或改变表观遗传修饰或剪接信号，与许多人类癌症有关。我们报告了一个首先通过桑格测序分析归类为具有 LLS 的家族。下一代测序（NGS）分析在 MLH1 外显子 6 中鉴定出一个 AluY5a 插入，导致外显子跳跃。这种剪接改变导致致病移码，在发生结直肠腺癌的患者中发现。因此，反转元件插入可能是癌症遗传学的一个重要但被低估的机制，可以在表型提示 LS 的患者中系统地进行测试，以准确评估家族风险和监测方法。
