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Molecular Diagnostics

Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma

British Journal of Cancer volume 125, pages 1533–1543 (2021)Cite this article

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Abstract

Background

Cabozantinib is an oral tyrosine kinase inhibitor in renal cell carcinoma (RCC), whose targets include oncogenic AXL and unique ligand GAS6. Critical gaps in basic knowledge need to be addressed to devise an exclusive biomarker and candidate when targeting the AXL/GAS6 axis.

Methods

To clarify the effects of the AXL/GAS6 axis on RCC, we herein performed a large-scale immunogenomic analysis and single-cell counts including various metastatic organs and histological subtypes of RCC. We further applied genome-wide mutation analyses and methylation arrays.

Results

Varying patterns of AXL and GAS6 expression were observed throughout primary RCC tumours and metastases. Scoring individual AXL/GAS6 levels in the tumour centre and invasive margin, namely, the AXL/GAS6 score, showed a good ability to predict the prognosis of clear cell RCC. Metastasis- and histological subtype-specific differences in the AXL/GAS6 score existed since lung metastasis and the papillary subtype were weakly related to the AXL/GAS6 axis. Cell-by-cell immunohistological assessments clarified an immunosuppressive environment in tumours with high AXL/GAS6 scores. Genomic alterations in the PI3K-mTOR pathway and DNA methylation profiling revealed distinct differences with the AXL/GAS6 score in ccRCC.

Conclusion

The AXL/GAS6 scoring system could predict the outcome of prognosis and work as a robust biomarker for the immunogenomic state in RCC.

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Fig. 1: Quantitative AXL and GAS6 evaluation and patient survival in ccRCC.
Fig. 2: Assessment of the AXL/GAS6 score and outcome of prognosis in ccRCC.
Fig. 3: Immunohistological assessment of the AXL/GAS6 score and tumour immune microenvironment.
Fig. 4: Metastasis-specific differences in AXL/GAS6 distribution and the tumour immune microenvironment.
Fig. 5: Somatic genomic alterations and methylation profiles related to the AXL/GAS6 axis.

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Acknowledgements

This study was supported by the Grant-in-Aid for Scientific Research (KAKENHI 20K18125 to KH; 18H04906, 18K19482 and 19H03792 to NT; 18K09150 to TS and 18H02939 to MO), the Takeda Science Foundation (NT), the Kobayashi Foundation for Cancer Research (NT), the SGH Cancer Research Grant (NT) and the Keio Gijuku Academic Development Funds (NT).

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Authors and Affiliations

  1. Department of Urology, Keio University School of Medicine, 160-8582, Tokyo, Japan

    Kyohei Hakozaki, Nobuyuki Tanaka, Kimiharu Takamatsu, Ryohei Takahashi, Yota Yasumizu, Toshiaki Shinojima, Ryuichi Mizuno & Mototsugu Oya

  2. Department of Diagnostic Pathology, Keio University Hospital, Tokyo, Japan

    Shuji Mikami

  3. Department of Urology, Saitama Medical University, Moroyama, Saitama, Japan

    Toshiaki Shinojima

  4. Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan

    Kazuhiro Kakimi

  5. Laboratory for Medical Science Mathematics, Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan

    Takashi Kamatani & Tatsuhiko Tsunoda

  6. Department of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Takashi Kamatani, Fuyuki Miya & Tatsuhiko Tsunoda

  7. Department of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan

    Takashi Kamatani

  8. Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Tatsuhiko Tsunoda

  9. Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan

    Eriko Aimono & Hiroshi Nishihara

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  1. Kyohei Hakozaki
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Contributions

NT, RM and MO designed the study. KH, KT, RT, YY and SM performed the experiments. EA and HN performed genome sequencing. TS, KK, TK, FM and TT provided conceptual advice. KH and NT wrote the manuscript.

Corresponding author

Correspondence to Nobuyuki Tanaka.

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Ethics approval and consent to participate

All procedures were performed in approval of the Research Ethics Committee of Keio University (Approval Nos.: 20180098 and 20190059) and in compliance with the 1964 Helsinki Declaration and present ethical standards. The samples were residual from a clinical examination without using any identifiable information of the individuals or the application of any intervention. Participation in the study was optional. Both written informed consent and passive (opt-out) informed consent procedures have been applied to the experimental use of human samples. Opt-out informed consent from patients was obtained by exhibiting the research information on our department website (Department of Urology, Keio University Hospital, Tokyo, Japan). All participant patients or families of deceased patients could withdraw consent by contacting the researcher with a 24-h phone number. The need to obtain written informed consent was waived if patients had finished their follow-up or had died, due to the study’s observational nature and the urgent need for cancer patient care. This was approved and reviewed by the Research Ethics Committee of Keio University, in accordance with the ethical guidelines for Medical and Health Research Involving Human Subjects (Public Notice of the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor and Welfare as of July 2018; https://www.lifescience.mext.go.jp/files/pdf/n2181_01.pdf).

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The authors declare no competing interests.

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Hakozaki, K., Tanaka, N., Takamatsu, K. et al. Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma. Br J Cancer 125, 1533–1543 (2021). https://doi.org/10.1038/s41416-021-01559-8

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