Department of Surgery, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, 3-1, Aoyama-cho, Kure City, Hiroshima, 737-0023, Japan.
Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
BMC Med Genet. 2020 Jul 1;21(1):141. doi: 10.1186/s12881-020-01079-x.
Lynch syndrome (LS), which is known as a hereditary cancer syndrome, is distinguished by microsatellite instability, represented by the altered number of repetitive sequences in the coding and/or non-coding region. Immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has been recognized as an useful technique for screening of LS. Previous study has shown that the assessment of IHC, however, requires specific caution due to variable staining patterns even without germline mutations in MMR genes.
A 48-year-old man, who had been treated for anaplastic astrocytoma, was referred to our department for the precise examination of progressing anemia. Whole-body examination revealed two advanced carcinomas in descending colon and stomach. A hypo-vascular mass lesion was detected in liver as well. Pathological diagnosis (on surgical specimens) was poorly differentiated adenocarcinoma in descending colon, moderately differentiated tubular adenocarcinoma in stomach, and liver metastasis, which is possibly from colon. It was suspected that this case would be Turcot's syndrome-type-1 due to its specific family history having two cases of colon cancer within the second relatives. Pathogenic frameshift mutations in codon 618 of MLH1 gene was identified. Immunohistochemical analyses (IHC) demonstrated complete loss of MLH1 immuno-expression as well as of PMS2 except for those in brain tumor. Although frameshift mutation was not found in MSH6 gene, histological expression of MSH6 was patchy in primary colon carcinoma and was completely lost in the metastatic site in liver. MSH6 expression in gastric carcinoma, a coincidental cancer in this case, was intact. An abnormal (C)8 region was identified by the cloned PCR of colon and liver tumors but not from gastric cancer. Frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene was also detected in liver metastasis.
This case supports a plausible mechanism, proposed by a previous literature, for the reduced expression of MSH6 in a somatic mutation manner, which might preferentially happen in colon cancer rather than in stomach carcinoma in MLH1/PMS2-deficient type of Turcot's syndrome type 1.
林奇综合征（LS）是一种遗传性癌症综合征，其特征是微卫星不稳定，表现为编码和/或非编码区域中重复序列数量的改变。DNA 错配修复（MMR）蛋白的免疫组化染色（如 MLH1、MSH2、MSH6 和 PMS2）已被认为是筛查 LS 的有用技术。先前的研究表明，由于即使在 MMR 基因没有种系突变的情况下，染色模式也存在差异，因此对 IHC 的评估需要特别谨慎。
一名 48 岁男性，曾因间变性星形细胞瘤接受治疗，因进行性贫血被转诊至我科进行精确检查。全身检查发现降结肠和胃有两处晚期癌。肝脏也发现一个低血管肿块病变。手术标本的病理诊断为降结肠癌低分化腺癌、胃中分化管状腺癌和肝转移，可能来自结肠。由于其特殊的家族史，有两个二级亲属患有结肠癌，因此怀疑该病例为 Turcot's 综合征 1 型。在 MLH1 基因的密码子 618 中发现了致病性移码突变。免疫组化分析（IHC）显示 MLH1 免疫表达完全缺失，除脑肿瘤外 PMS2 也完全缺失。尽管 MSH6 基因未发现移码突变，但原发性结肠癌的 MSH6 组织学表达呈斑片状，在肝转移部位完全缺失，而在胃的偶发癌中表达完整。克隆 PCR 显示结肠和肝肿瘤存在异常（C）8 区，但在胃癌中不存在。在肝转移中也检测到 MSH6 基因外显子 5 中（C）8 区的移码突变。
该病例支持先前文献提出的一种可能的机制，即 MSH6 的表达降低是体细胞突变的结果，这种突变可能更倾向于发生在 MLH1/PMS2 缺陷型 Turcot's 综合征 1 型的结肠癌中，而不是胃腺癌中。
