Claudins are central components of tight junctions that regulate epithelial cell barrier function and polarity. Altered claudin expression patterns have been demonstrated in numerous cancer types and lineage-specific claudins have been proposed as therapy targets. The objective of this study was to assess claudin 6 (CLDN6) and claudin 18 isoform 2 (CLDN18.2) expression in human non-small cell lung cancer (NSCLC).

Transcript levels were evaluated based on gene expression microarray data from a fresh-frozen NSCLC tissue cohort (n=196). Protein expression levels of CLDN6 and CLDN18.2 were examined by immunohistochemistry on a tissue microarray (n=355), and analyzed with regard to frequency distribution and association with clinical parameters.

High mRNA levels of CLDN6 and total CLDN18 were observed in subsets of non-squamous lung carcinomas. Correspondingly, distinct membranous positivity of CLDN6 (6.5%) and CLDN18.2 (3.7%) was displayed by virtually non-overlapping subgroups of adenocarcinomas and large cell carcinomas, while pneumocytes and bronchial epithelial cells were consistently negative. CLDN18.2 positive tumors were enriched among slowly proliferating, TTF1-negative adenocarcinomas, suggesting that isoform-specific claudin expression may delineate a specific subtype. Noteworthy, high CLDN6 mRNA as well as protein expression was associated with worse prognosis in lung adenocarcinoma.

In conclusion, distinct CLDN6 and CLDN18.2 positivity was observed in minor subsets of non-squamous NSCLC, indicating that tumor-specific claudin expression may define molecular subtypes associated with clinical parameters. These findings encourage further clinical exploration of targeting ectopic claudin expression as a valuable treatment concept in NSCLC.

Citation Format: Johanna SM Mattsson, Patrick Micke, Karolina Edlund, Miriam Lohr, Karin Jirström, Anders Berglund, Johan Botling, Jörg Rahnenfuehrer, Millaray Marincevic, Fredrik Pontén, Simon Ekman, Jan G. Hengstler, Stefan Wöll, Ugur Sahin, Özlem Türeci. Ectopic claudin 6 and 18.2 expression as potential treatment target in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A37.