Yamaguchi Tatsuro, Wakatsuki Tomokazu, Kikuchi Mari, Horiguchi Shin-Ichiro, Akagi Kiwamu
Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital.
Hereditary Tumor Research Project, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
Jpn J Clin Oncol. 2017 Jun 1;47(6):576-580. doi: 10.1093/jjco/hyx023.
The proband was a 67-year-old man with transverse and sigmoid colon cancer. Microsatellite instability analysis revealed a high frequency of microsatellite instability, and immunohistochemical staining showed the absence of both MLH1 and PMS2 proteins in the sigmoid colon cancer tissue specimens from the patient. DNA sequencing revealed a nucleotide substitution c.543C>T in MLH1, but this variant did not substitute an amino acid. The MLH1 c.543C>T variant was located 3 bases upstream from the end of exon 6 and created a new splice donor site 4 bases upstream from the end of exon 6. Consequently, the last 4 bases of exon 6 were deleted and frameshift occurred. Thus, the MLH1 c.543C>T silent mutation is considered 'pathogenic'.
先证者是一名67岁患有横结肠癌和乙状结肠癌的男性。微卫星不稳定性分析显示微卫星不稳定性频率较高，免疫组织化学染色显示患者乙状结肠癌组织标本中MLH1和PMS2蛋白均缺失。DNA测序显示MLH1基因存在一个核苷酸替换c.543C>T，但该变异并未替换氨基酸。MLH1基因的c.543C>T变异位于外显子6末端上游3个碱基处，并在外显子6末端上游4个碱基处产生了一个新的剪接供体位点。因此，外显子6的最后4个碱基被删除并发生了移码。所以，MLH1基因的c.543C>T沉默突变被认为是“致病性的”。
