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

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...

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Published in:Virchows Archiv : an international journal of pathology 2021-03, Vol.478 (3), p.569-579
Main Authors: Takashima, Tsuyoshi, Sakamoto, Naoya, Murai, Junko, Taniyama, Daiki, Honma, Ririno, Ukai, Shoichi, Maruyama, Ryota, Kuraoka, Kazuya, Rajapakse, Vinodh N., Pommier, Yves, Yasui, Wataru
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container_title Virchows Archiv : an international journal of pathology
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creator Takashima, Tsuyoshi
Sakamoto, Naoya
Murai, Junko
Taniyama, Daiki
Honma, Ririno
Ukai, Shoichi
Maruyama, Ryota
Kuraoka, Kazuya
Rajapakse, Vinodh N.
Pommier, Yves
Yasui, Wataru
description 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.
doi_str_mv 10.1007/s00428-020-02840-6
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identifier ISSN: 0945-6317
ispartof Virchows Archiv : an international journal of pathology, 2021-03, Vol.478 (3), p.569-579
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subjects Antineoplastic Agents - therapeutic use
Biomarkers
Biomarkers, Tumor - analysis
Biomarkers, Tumor - genetics
Carboplatin
Cell Line, Tumor
Cisplatin
Clinical Decision-Making
Cytarabine
Damage
Databases, Genetic
Deoxyribonucleic acid
DNA
DNA Damage
DNA helicase
Doxorubicin
Drug Resistance, Neoplasm
Drugs
Etoposide
Female
Gemcitabine
Gene expression
Genomes
Humans
Immune system
Immunohistochemistry
Immunosuppressive agents
Inhibitors
Lymphocytes
Lymphocytes B
Lymphocytes T
Macrophages
Male
Medicine
Medicine & Public Health
Neoplasms - drug therapy
Neoplasms - enzymology
Neoplasms - genetics
Neoplasms - pathology
Nuclear Proteins - analysis
Nuclear Proteins - genetics
Organs
Original Article
Pathology
Platinum
Predictive Value of Tests
Quality in Pathology
Replication
Reproducibility of Results
Ribonucleic acid
RNA
RNA helicase
RNA-Seq
Tumorigenesis
Tumors
title Immunohistochemical analysis of SLFN11 expression uncovers potential non-responders to DNA-damaging agents overlooked by tissue RNA-seq
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