Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
Jpn J Clin Oncol. 2019 May 1;49(5):477-480. doi: 10.1093/jjco/hyz031.
The proband was a 62-year-old man with ureter cancer. He had a history of metachronous colorectal and gastric cancer. Immunohistochemical staining showed the absence of both MSH2 and MSH6 proteins in the ureter cancer and other available cancer tissue specimens. Genetic testing was conducted to identify the causative genes of hereditary gastrointestinal cancer syndromes including mismatch repair genes. We detected a germline variant, c.2635-3delC, within the splice acceptor site of exon 16, in the MSH2 gene. To investigate whether this variant affected splicing of the gene, RNA sequencing was performed using blood samples. We observed a substantial amount of the transcripts that lacked proper splicing of intron 15 in the indexed case, whereas, a very low amount of such aberrant transcripts was detected in the controls, strongly indicating an association between the variant and splicing defect. These results indicate that MSH2 c.2635-3delC affects normal splicing and might be a cause of Lynch syndrome.
先证者为 62 岁男性，患有输尿管癌。他有结直肠和胃癌的异时性病史。免疫组织化学染色显示输尿管癌和其他可用的癌组织标本中均缺乏 MSH2 和 MSH6 蛋白。进行了遗传检测，以确定包括错配修复基因在内的遗传性胃肠道癌综合征的致病基因。我们在 MSH2 基因的外显子 16 的剪接受体位点检测到一个种系变异，c.2635-3delC。为了研究该变异是否影响基因的剪接，使用血液样本进行了 RNA 测序。我们观察到索引病例中有大量的转录本缺乏 15 号内含子的适当剪接，而在对照组中则检测到非常少量的这种异常转录本，这强烈表明该变异与剪接缺陷之间存在关联。这些结果表明 MSH2 c.2635-3delC 影响正常剪接，可能是 Lynch 综合征的原因。
