Colitis‐associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy

Abstract

Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy 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 ATrich 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.

Claudin-18 expression in small bowel adenocarcinoma: a clinico-pathologic study

“…Conversely, SBAs expressed CLDN18 more frequently than colorectal carcinomas (CRCs) [27], but, of note, expression rates became similar when CRC cases were enriched, as our series was, with inflammatory bowel disease (IBD)-associated tumours. Moreover, as previously described by Iwaya et al in the colorectal counterpart [17], we detected CLDN18 expression in tumour-adjacent metaplastic mucosa and, focally, in some scattered, apparently normal crypts of CrD patients only. In our cohort, mostly in CrD-SBAs, CLDN18 positivity was also observed in some cancer-adjacent dysplastic lesions, and in most cases there was concordance in CLDN18 expression between the dysplastic growth and the invasive neoplasm.…”

“…Furthermore, we found a statistically significant association of CLDN18 with both the expression of the non-intestinal markers MUC5AC and CK7 separately evaluated and the MUC5AC+/CK7+ immunophenotype. Interestingly, a correlation of CLDN18 and MUC5AC was previously described in IBD-associated CRCs [ 17 27 ]. The increased expression of other metaplastic markers (e.g.…”

“…Particularly, claudin-18 (CLDN18), which can be found in two splicing variants, has a specific topographic expression in healthy tissues, with claudin-18.1 being expressed in the lung and claudin-18.2 in the stomach [ 14 ]. In addition, claudin-18.2 was also identified in several epithelial neoplasms, including gastric, pancreatobiliary, oesophageal, colorectal, ovarian and non-small cell lung carcinomas [ 15 16 17 18 ]. However, to the best of our knowledge, no study has hitherto investigated CLDN18 expression in SBAs.…”

Development and comparison of 68Ga/18F/64Cu-labeled nanobody tracers probing Claudin18.2

“…Aberrant activation or expression of Claudin18.2 was also found in non-small-cell lung cancer and colitis-associated colorectal adenocarcinomas. 27 , 28 These results indicate that CLDN18.2-targeted diagnostic or therapeutic agents would be in principle eligible for a considerable number of tumors. 29 With close collaboration with oncologists at the hospital, we can investigate the diagnostic accuracies of the reported tracers in broad types of tumors in the future.…”

Claudin18.2 expression and clinicopathological features in cytology effusion specimens from gastric adenocarcinoma: A comparative study with tissue specimens

“…At least 27 CLDN isoforms have been discovered in distinct human organ systems, and their altered function may contribute to tumor carcinogenesis in these tissues 8 . For the subtype, Claudin 18 splice variant 2 (CLDN18.2) is specific to the stomach 9 . According to several retrospective studies, CLDN18.2 levels reach 34% in American and 24% in Asian samples 5 .…”