Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by
- PDF / 8,131,411 Bytes
- 11 Pages / 595.276 x 790.866 pts Page_size
- 15 Downloads / 154 Views
ORIGINAL ARTICLE
Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by tissue RNA-seq Tsuyoshi Takashima 1 & Naoya Sakamoto 1 & Junko Murai 2 & Daiki Taniyama 1 & Ririno Honma 1 & Shoichi Ukai 1 & Ryota Maruyama 1 & Kazuya Kuraoka 3 & Vinodh N. Rajapakse 4 & Yves Pommier 4 & Wataru Yasui 1 Received: 27 February 2020 / Revised: 17 April 2020 / Accepted: 3 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 nontumor 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, SLFN11negative 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. Keywords DNA damage . DNA repair . Drug resistance . Immunohistochemistry . SLFN11 This article is part of the Topical Collection on Quality in Pathology Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00428-020-02840-6) contains supplementary material, which is available to authorized users. * Wataru Yasui [email protected] 1
Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
2
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
3
Department of Diagnostic Pathology, National Hospital Organization, Kure Medical Center and Chugoku Cancer Center, Kure city, Hiroshima 737-0023, Japan
4
Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research
Data Loading...
