Yamaguchi Junya, Sato Yuri, Kita Mizuho, Nomura Sachio, Yamamoto Noriko, Kato Yo, Ishikawa Yuichi, Arai Masami
Clinical Genetic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo.
Clinical Genetic Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo Department of Clinical Research, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo.
Jpn J Clin Oncol. 2015 Oct;45(10):993-7. doi: 10.1093/jjco/hyv103. Epub 2015 Jul 16.
Lynch syndrome is an autosomal dominantly inherited disease that is characterized by a predisposition to cancers, mainly colorectal cancer. Germline mutations of DNA mismatch repair genes such as MLH1, MSH2, MSH6 and PMS2 have been described in patients with Lynch syndrome. Here, we report deletion of 2 bp in the splice donor site of the MLH1 exon 6 (c.545+4_545+5delCA) in a 48-year-old Japanese woman with Lynch syndrome. RT-PCR direct sequencing analysis revealed that this mutation led to an increase in the level of an MLH1 transcript in which exon 6 was skipped, and may cause a frameshift (p.E153FfsX8). Therefore, this mutation appears to be pathogenic and is responsible for Lynch syndrome. Additionally, analysis of the patient's tumor cells indicated microsatellite instability high phenotype and loss of the MLH1 and PMS2 proteins. To our knowledge, this is a germline splice site mutation of MLH1 that has not been reported previously.
林奇综合征是一种常染色体显性遗传病，其特征是易患癌症，主要是结直肠癌。林奇综合征患者中已发现DNA错配修复基因如MLH1、MSH2、MSH6和PMS2的种系突变。在此，我们报告一名48岁的日本林奇综合征女性患者中，MLH1外显子6的剪接供体位点缺失2个碱基对（c.545+4_545+5delCA）。逆转录聚合酶链反应直接测序分析显示，该突变导致跳过外显子6的MLH1转录本水平增加，并可能导致移码（p.E153FfsX8）。因此，该突变似乎具有致病性，是林奇综合征的病因。此外，对患者肿瘤细胞的分析表明微卫星高度不稳定表型以及MLH1和PMS2蛋白缺失。据我们所知，这是此前未报道过的MLH1种系剪接位点突变。
