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Claudin18.2 expression in pulmonary mucinous adenocarcinoma

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Abstract

Background

Pulmonary invasive mucinous adenocarcinoma (IMA) is a unique type of lung adenocarcinoma with a high recurrence rate and limited treatment strategies. The tight-junction-associated protein claudin18.2 is a new therapeutic target for several solid tumors. This study aimed to detect the expression of claudin18.2 in IMA and its clinicopathological association with the disease.

Methods

 The expression of claudin18.2 was immunohistochemically evaluated in an IMA cohort of 84 patients, who underwent partial pneumonectomy between January 2017 and December 2021. Positive staining for claudin18.2 was defined as ≥ 10% of tumor cells showing ≥ 1 + membrane staining or any ≥ 2 + membrane staining.

Results

Claudin18.2 was detected in 76.2% (64/84) of IMA patients, significantly higher than that in non-mucinous adenocarcinoma (NMA). 46.4% (39/84) of the IMA patients met the enrollment criteria of the clinical trials of monoclonal antibodies (≥ 75% of tumor cells demonstrating ≥ 2 + staining intensity). Positive staining for claudin18.2 was significantly associated with smaller tumor size (p = 0.010), less pleural invasion (p = 0.019), and earlier pN stage (p < 0.001). Expression of claudin18.2 was not related to prognosis in multivariate analysis.

Conclusions

To summarize, in this study we found that claudin18.2 was remarkably highly expressed in IMA and the overexpression was associated with low invasive capacity. Thus, this protein appears to be a promising therapeutic target and deserves further investigation in IMA patients.

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Data availability

The data analyzed during the current study are available from the corresponding author on reasonable request.

References

  • Arpa G, Fassan M, Guerini C, Quaquarini E, Grillo F, Angerilli V, Guzzardo V, Lonardi S, Bergamo F, Lenti MV, Pedrazzoli P, Paulli M, Di Sabatino A, Vanoli A (2022) Claudin-18 expression in small bowel adenocarcinoma: a clinico-pathologic study. Virchows Arch 481(6):853–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baek JH, Park DJ, Kim GY, Cheon J, Kang BW, Cha HJ, Kim JG (2019) Clinical Implications of Claudin18.2 Expression in Patients With Gastric Cancer. Anticancer Res 39(12):6973–6979

    Article  PubMed  Google Scholar 

  • Cao W, Xing H, Li Y, Tian W, Song Y, Jiang Z, Yu J (2022) Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res 10(1):38

    Article  PubMed  PubMed Central  Google Scholar 

  • Duruisseaux M, Antoine M, Rabbe N, Rodenas A, Mc Leer-Florin A, Lacave R, Poulot V, Duchene B, Van Seuningen I, Cadranel J, Wislez M (2017) Lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma of the lung exhibit specific mucin expression in relation with oncogenic drivers. Lung Cancer 109:92–100

    Article  PubMed  Google Scholar 

  • Guo M, Tomoshige K, Meister M, Muley T, Fukazawa T, Tsuchiya T, Karns R, Warth A, Fink-Baldauf IM, Nagayasu T, Naomoto Y, Xu Y, Mall MA, Maeda Y (2017) Gene signature driving invasive mucinous adenocarcinoma of the lung. EMBO Mol Med 9(4):462–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwaya M, Hayashi H, Nakajima T, Matsuda K, Kinugawa Y, Tobe Y, Tateishi Y, Iwaya Y, Uehara T, Ota H (2021) Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy. Histopathology 79(2):227–237

    Article  PubMed  Google Scholar 

  • Kominsky SL (2006) Claudins: emerging targets for cancer therapy. Expert Rev Mol Med 8(18):1–11

    Article  PubMed  Google Scholar 

  • Liu J, Yang H, Yin D, Jia Y, Li S, Liu Y (2022) Expression and prognostic analysis of CLDN18 and Claudin18.2 in lung adenocarcinoma. Pathol Res Pract 238:154068

    Article  CAS  PubMed  Google Scholar 

  • Lordick F, Al-Batran SE, Ganguli A, Morlock R, Sahin U, Tureci O (2021) Patient-reported outcomes from the phase II FAST trial of zolbetuximab plus EOX compared to EOX alone as first-line treatment of patients with metastatic CLDN18.2+ gastroesophageal adenocarcinoma. Gastric Cancer 24(3):721–730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo J, Chimge NO, Zhou B, Flodby P, Castaldi A, Firth AL, Liu Y, Wang H, Yang C, Marconett CN, Crandall ED, Offringa IA, Frenkel B, Borok Z (2018) CLDN18.1 attenuates malignancy and related signaling pathways of lung adenocarcinoma in vivo and in vitro. Int J Cancer 143(12):3169–3180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuda M, Sentani K, Noguchi T, Hinoi T, Okajima M, Matsusaki K, Sakamoto N, Anami K, Naito Y, Oue N, Yasui W (2010) Immunohistochemical analysis of colorectal cancer with gastric phenotype: claudin-18 is associated with poor prognosis. Pathol Int 60(10):673–680

    Article  PubMed  Google Scholar 

  • Micke P, Mattsson JSM, Edlund K, Lohr M, Jirström K, Berglund A, Botling J, Rahnenfuehrer J, Marincevic M, Pontén F, Ekman S, Hengstler J, Wöll S, Sahin U, Türeci Ö (2014) Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer. Int J Cancer 135(9):2206–2214

    Article  CAS  PubMed  Google Scholar 

  • Sahin U, Koslowski M, Dhaene K, Usener D, Brandenburg G, Seitz G, Huber C, Türeci Ö (2008) Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res 14(23):7624–7634

    Article  CAS  PubMed  Google Scholar 

  • Sahin U, Türeci Ö, Manikhas G, Lordick F, Rusyn A, Vynnychenko I, Dudov A, Bazin I, Bondarenko I, Melichar B, Dhaene K, Wiechen K, Huber C, Maurus D, Arozullah A, Park JW, Schuler M, Al-Batran S-E (2021) FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol 32(5):609–619

    Article  CAS  PubMed  Google Scholar 

  • Shimobaba S, Taga S, Akizuki R, Hichino A, Endo S, Matsunaga T, Watanabe R, Yamaguchi M, Yamazaki Y, Sugatani J, Ikari A (2016) Claudin-18 inhibits cell proliferation and motility mediated by inhibition of phosphorylation of PDK1 and Akt in human lung adenocarcinoma A549 cells. Biochim Biophys Acta 1863(6 Pt A):1170–1178

    Article  CAS  PubMed  Google Scholar 

  • Türeci Ö, Koslowski M, Helftenbein G, Castle J, Rohde C, Dhaene K, Seitz G, Sahina U (2011) Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals. Gene 481(2):83–92

    Article  PubMed  Google Scholar 

  • Wang X, Zhang C-S, Dong X-Y, Hu Y, Duan B-J, Bai J, Wu Y-Y, Fan L, Liao X-H, Kang Y, Zhang P, Li M-Y, Xu J, Mao Z-J, Liu H-T, Zhang X-L, Tian L-F, Li E-X (2022) Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma. World J Gastrointest Oncol 14(7):1252–1264

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu B, Liu F, Liu Q, Shi T, Wang Z, Wu N, Xu X, Li L, Fan X, Yu L, Liu B, Wei J (2020) Highly expressed Claudin18.2 as a potential therapeutic target in advanced gastric signet-ring cell carcinoma (SRCC). J Gastrointest Oncol 11(6):1431–1439

    Article  PubMed  PubMed Central  Google Scholar 

  • Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, Park BJ, Rusch VW, Travis WD (2011) Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol 24(5):653–664

    Article  CAS  PubMed  Google Scholar 

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Funding

This study is supported by the National High Level Hospital Clinical Research Funding 2023-PUMCH-F-004 (D.G.), 2022-PUMCH-B-062 (J.S.), 2022-PUMCH-D-002 (D.G) and CAMS Innovation Fund for Medical Sciences (CIFMS) 2021-I2M-1-053 (D.G. and Z.-Y.L.).

Author information

Author notes

  1. Yuming Wang and Yike Gao have contributed equally.

  2. Jian Sun and Dan Guo have contributed equally.

Authors and Affiliations

  1. Department of Pathology, Molecular Pathology Research Centre, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, People’s Republic of China

    Yuming Wang, Yike Gao, Zhiwen Zhang, Mei Li, Jian Sun & Zhiyong Liang

  2. Clinical Biobank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

    Zixin Zhang, Anqi Wang, Kun Zhao, Miao Zhang, Sumei Zhang & Dan Guo

Authors
  1. Yuming Wang
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  2. Yike Gao
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Contributions

YMW, ZWZ, and YKG gathered the cohort, interpreted the immunohistochemical staining, and analyzed the clinical and pathology data. YMW visualized the data and wrote the original draft. ZWZ and YKG edited the manuscript. ZXZ, AQW, KZ, and MZ collected materials, prepared the sections, and performed immunohistochemical staining. SMZ participated in the pre-study of tissue microarrays. JS and DG participated in the study design and supervision. ZYL provided resources and reviewed the study. All authors discussed the results and contributed to the final manuscript.

Corresponding authors

Correspondence to Jian Sun or Dan Guo.

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Conflict of interest

The authors declare no competing interests with respect to the research.

Ethics approval

This study was approved by the Institutional Review Board of Peking Union Medical College Hospital (protocol number: JS-3553) and all the research was performed in accordance with relevant guidelines.

Informed consent

Informed consent was obtained for all patients enrolled in the study.

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Wang, Y., Gao, Y., Zhang, Z. et al. Claudin18.2 expression in pulmonary mucinous adenocarcinoma. J Cancer Res Clin Oncol 149, 12923–12929 (2023). https://doi.org/10.1007/s00432-023-05150-x

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