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Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by tissue RNA-seq

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An Editorial to this article was published on 10 February 2021

Abstract

DNA-damaging agents include first-line drugs such as platinum (cisplatin, carboplatin), topoisomerase inhibitors (etoposide, doxorubicin), and replication inhibitors (cytarabine, gemcitabine). Despite their wide and long usage, there is no clinically available biomarker to predict responses to these drugs. Schlafen 11 (SLFN11), a putative DNA/RNA helicase, recently emerged as a dominant determinant of sensitivity to these drugs by enforcing the replication block in response to DNA damage. Since the clinical importance of SLFN11 is implicated, a comprehensive analysis of SLFN11 expression across human organs will provide a practical resource to develop the utility of SLFN11 in the clinic. In this study, we established a scoring system of SLFN11 expression by immunohistochemistry (IHC) and assessed SLFN11 expression in ~ 700 malignant as well as the adjacent non-tumor tissues across 16 major human adult organs. We found that the SLFN11 expression is tissue specific and varies during tumorigenesis. Although The Cancer Genome Atlas (TCGA) is a prevailing tool to assess gene expression in various malignant and normal tissues, our IHC data exhibited obvious discrepancy from the TCGA data in several organs. Importantly, SLFN11-negative tumors, potentially non-responders to DNA-damaging agents, were largely overrated in TCGA because TCGA samples are a mixture of infiltrating immune cells, including T cells, B cells, and macrophages, which have strong SLFN11 expression. Thus, our study reveals the significance of immunohistochemical procedures for evaluating expression of SLFN11 in patient samples and provides a robust resource of SLFN11 expression across adult human organs.

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Acknowledgments

We thank Mr. Shinichi Norimura for his technical assistance. This work was carried out with kind cooperation from the Research Center for Molecular Medicine of the Faculty of Medicine of Hiroshima University. We also thank the Analysis Center of Life Science of Hiroshima University for the use of their facilities.

Funding

This work was supported by Grants-in-Aid for Scientific Research (JP15H04713 and JP16K08691 to W.Y., JP16H06999 to N.S.) and (19H03505 to J.M.), Challenging Exploratory Research (26670175, JP16K15247 to W.Y.) from the Japan Society for the Promotion of Science, AMED (Japan Agency for Medical Research and Development) Project for Cancer Research and Therapeutic Evolution (to J.M.), and a research grant from The Uehara Memorial Foundation (to J.M.). Y.P. and V.R. are supported by the Center for Cancer Research, the Intramural program of the US National Cancer Institute, NIH (Z01 BC 006150).

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Authors and Affiliations

  1. Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 734-8551, Japan

    Tsuyoshi Takashima, Naoya Sakamoto, Daiki Taniyama, Ririno Honma, Shoichi Ukai, Ryota Maruyama & Wataru Yasui

  2. Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, 997-0052, Japan

    Junko Murai

  3. Department of Diagnostic Pathology, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Kure city, Hiroshima, 737-0023, Japan

    Kazuya Kuraoka

  4. Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Vinodh N. Rajapakse & Yves Pommier

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  1. Tsuyoshi Takashima
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Contributions

N.S., J.K., and Y.P. designed the study. T.T., D.T., and K.K. provided the patients’ clinical information. T.T., D.T., R.H., S.U., R.M., and V.N.R. performed the experiments and acquired the data. N.S., J.K., Y.P., and W.Y. interpreted the results. T.T., N.S., J.M., V.N.R., Y.P., and W.Y. drafted and edited the manuscript. All the authors read and approved the manuscript and agree to be accountable for all aspects of the research and in ensuring that the accuracy or integrity of any part of the work is appropriately investigated and resolved.

Corresponding author

Correspondence to Wataru Yasui.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethics approval

This study was approved by the Ethics Committee of Kure Medical Center and Chugoku Cancer Center (Kure, Japan, no. 2019-36) and conformed to the ethical guidelines of the Declaration of Helsinki.

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All samples were obtained with patient consent.

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Statistical differences were evaluated using the Pearson’s test. Statistical analyses were conducted primarily using GraphPad Prism software (GraphPad Software Inc.).

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Takashima, T., Sakamoto, N., Murai, J. et al. Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by tissue RNA-seq. Virchows Arch 478, 569–579 (2021). https://doi.org/10.1007/s00428-020-02840-6

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