结肠炎相关结直肠腺癌常表达 claudin 18 亚型 2：对 claudin 18.2 单克隆抗体治疗的影响。
Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy.
机构信息
Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.
Department of Pathology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.
出版信息
Histopathology. 2021 Aug;79(2):227-237. doi: 10.1111/his.14358. Epub 2021 Apr 21.
AIMS
Claudin 18 (CLDN18) is a member of the claudin family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell-cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells, and is frequently expressed at high levels in gastric adenocarcinoma. On the basis of this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2-positive gastro-oesophageal adenocarcinoma. Colitis-associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of human epidermal growth factor receptor 2 (HER2) inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs.
METHODS AND RESULTS
We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients, and compared the expression profile with that of a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 expression and CLDN18.2 expression were validated by reverse transcription polymerase chain reaction (PCR) in paraffin-embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CACs and in 5% (3/56) of sporadic CRCs (P = 0.004), and CLDN18-positive CACs were more likely to have lymph node metastasis than CLDN18-negative CACs (67% versus 36%; P = 0.017). CLDN18 expression was significantly associated with MUC5AC expression (P < 0.001) and loss of special AT-rich sequence-binding protein 2 expression (P = 0.005) in CACs. CLDN18.2 was expressed in CRCs that were immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2, and no differences were identified in sporadic CRCs.
CONCLUSIONS
These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy.
目的
Claudin 18（CLDN18）是细胞表面蛋白 Claudin 家族的成员，广泛表达于上皮细胞，在细胞间黏附中发挥作用。CLDN18 亚型 2（CLDN18.2）特异性表达于胃上皮细胞，在胃腺癌中常高水平表达。基于此，针对 CLDN18.2 阳性的胃食管腺癌患者开发了靶向单克隆抗体 zolbetuximab。炎症性肠病相关结直肠癌（CAC）往往失去肠标志物，表现出异常胃黏蛋白表达。此外，人表皮生长因子受体 2（HER2）抑制剂治疗结直肠癌的临床试验正在进行中。然而，CLDN18.2 和 HER2 的表达谱尚未在一系列人类 CAC 中描述。
方法和结果
我们对 55 例炎症性肠病患者的 56 例连续 CAC 进行了 CLDN18 和 HER2 的免疫组织化学检测，并将表达谱与 56 例散发性结直肠腺癌（CRC）的对照组进行了比较。我们通过逆转录聚合酶链反应（PCR）在石蜡包埋的 CRC 组织中验证了 CLDN18.1 和 CLDN18.2 的表达。CLDN18 在 27%（15/56）的 CAC 和 5%（3/56）的散发性 CRC 中为阳性（P=0.004），CLDN18 阳性 CAC 比 CLDN18 阴性 CAC 更有可能发生淋巴结转移（67%比 36%；P=0.017）。CLDN18 表达与 CAC 中 MUC5AC 表达显著相关（P<0.001），与特殊 AT 富含序列结合蛋白 2 表达缺失相关（P=0.005）。CLDN18.2 在免疫反应性 CLDN18 的 CRC 中表达。只有 4%的 CAC 对 HER2 免疫反应，散发性 CRC 中无差异。
结论
这些发现表明，某些 CAC 病例可能是靶向 zolbetuximab 治疗的候选者。
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