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

Kyohei Hakozaki, Nobuyuki Tanaka, Kimiharu Takamatsu, Ryohei Takahashi, Yota Yasumizu, Shuji Mikami, Toshiaki Shinojima, Kazuhiro Kakimi, Takashi Kamatani, Fuyuki Miya, Tatsuhiko Tsunoda, Eriko Aimono, Hiroshi Nishihara, Ryuichi Mizuno, Mototsugu Oya

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1533-1543
Number of pages11
JournalBritish Journal of Cancer
Volume125
Issue number11
DOIs
Publication statusPublished - 2021 Nov 23
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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