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Heterogeneity of molecular subtyping and therapy-related marker expression in primary tumors and paired lymph node metastases of small cell lung cancer

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Abstract

The classification of molecular subtypes and the identification of targetable molecules have been proposed for small cell lung cancer (SCLC) patients. Our aim was to investigate whether the expression of these markers evaluated using lymph node (LN) metastases represents that of primary tumors. We enrolled 46 surgically resected SCLC patients’ primary tumors and paired mediastinal LN metastases. The protein expression of subtype-defining markers (ASCL1, NEUROD1, POU2F3, and YAP1) and therapeutic markers (DLL3, MYC, PD-L1, and MHC I) was examined by immunohistochemistry and was correlated with clinicopathological parameters and prognoses. In primary and metastatic tumors, the expression of these markers was 78.3% and 87.0%, 50.0% and 63.0%, 13.0% and 6.5%, 17.4% and 15.2%, 84.8% and 87.0%, 17.4% and 6.5%, 50.0% and 34.8%, and 60.9% and 37.0%, respectively. Positive tumor PD-L1 expression was less present in LN metastases (p = 0.015), and the same was true for MHC I expression (p = 0.036). NEUROD1 and DLL3 expression levels in metastatic tumors were stronger (p < 0.001 and p = 0.002, respectively); conversely, POU2F3, MYC, PD-L1, and MHC I expression levels were weaker (p = 0.018, p = 0.019, p = 0.001, and p < 0.001, respectively). In 15 (32.6%) patients, we observed a change in the molecular subtyping pattern, and a higher number of neuroendocrine (NE)-high phenotype patients were diagnosed when using the LN specimens (91.3% vs. 84.8%). TNM stage and postoperative chemotherapy were independent prognostic factors in surgically resected SCLC patients, and no prognostic differences were found among molecular subtypes. This study highlights the discordance of subtype-specific proteins and therapeutic markers between SCLC primary tumors and LN metastases. Additionally, our findings have therapeutic and prognostic implications and warrant further clinical investigation.

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Data are available upon reasonable request. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.

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Funding

This work was supported by the Science Foundation of Peking University Cancer Hospital (PY202303), the General Program of National Natural Science Foundation of China (82073247), the Beijing Municipal Administration of Hospitals Incubating Program (PX2019038), and the Beijing Youth Program for Outstanding Talents (2018000021469G262).

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  1. Yanli Zhu and Wenhao Ren are contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Institute, Beijing, China

    Yanli Zhu, Wenhao Ren, Jianghua Wu, Xiao Hu, Haiyue Wang, Kaiwen Chi & Dongmei Lin

  2. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department I of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China

    Sheng Li & Minglei Zhuo

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  1. Yanli Zhu
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Contributions

Y.Z.: conceptualization, investigation, project administration, writing-original draft, writing-review and editing. W.R.: data curation, conceptualization, writing-review and editing. S.L.: resources, writing-review and editing, funding acquisition. J.W.: methodology, validation, writing-review and editing. X.H.: data curation, methodology, writing-review and editing. H.W.: resources, conceptualization, writing-review and editing. K.C.: investigation, validation, writing-review and editing. M.Z.: conceptualization, writing-review and editing, supervision. D.L.: conceptualization, methodology, formal Analysis, writing-review and editing, visualization, supervision.

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Correspondence to Dongmei Lin.

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Zhu, Y., Ren, W., Li, S. et al. Heterogeneity of molecular subtyping and therapy-related marker expression in primary tumors and paired lymph node metastases of small cell lung cancer. Virchows Arch (2024). https://doi.org/10.1007/s00428-024-03754-3

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