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A New Thinking: Deciphering the Aberrance and Clinical Implication of IGF Axis Regulation Pattern in Clear Cell Renal

Aimin Jiang1, Xiaofeng Wu1, Desheng Wang2

  • 1Department of Urology, Changhai Hospital, Naval Medical University, (Second Military Medical University), Shanghai, China.

Frontiers in Immunology
|August 8, 2022
PubMed
Abstract

Insights

Insulin-like growth factor (IGF) regulators are crucial in cancer, including clear cell renal cell carcinoma (ccRCC). This study identifies IGF regulator-driven subtypes in ccRCC, revealing distinct immune and metabolic profiles, and proposes SHC1 as a therapeutic target.

Area of Science:

  • Oncology
  • Genomics
  • Immunology

Background:

  • Insulin-like growth factor (IGF) regulators are implicated in various biological processes and hold potential for cancer treatment.
  • The specific roles and implications of IGF regulators in cancers, particularly clear cell renal cell carcinoma (ccRCC), remain largely uncharacterized.

Purpose of the Study:

  • To systematically analyze the expression, prognostic value, genomic variations, and functional implications of IGF regulator genes across various cancers.
  • To classify ccRCC into distinct subtypes based on IGF regulator gene expression and investigate their associated immune microenvironment, metabolic patterns, and clinical characteristics.
  • To develop a prognostic risk model for ccRCC and evaluate SHC1 as a potential therapeutic target.

Main Methods:

  • Utilized The Cancer Genome Atlas (TCGA) data for pan-cancer analysis of IGF regulator genes.
  • Applied unsupervised clustering to stratify ccRCC into three subtypes (IPCS1, IPCS2, IPCS3) based on IGF regulator expression.
  • Investigated immune microenvironment, immunotherapy response, metabolic profiles, clinical characteristics, genomic mutations, and drug sensitivity for each subtype.
  • Constructed and validated a prognostic risk model and comprehensively analyzed SHC1 expression and its correlation with ccRCC outcomes.

Main Results:

  • IGF regulator genes are upregulated in multiple cancer types and associated with copy number variations and pathway dysregulation.
  • Three distinct ccRCC subtypes (IPCS1, IPCS2, IPCS3) exhibit differential clinical profiles, with IPCS3 showing higher stage, worse survival, activated metabolism, higher tumor mutation burden, and lower immune activity.
  • IPCS3 ccRCC demonstrates poor response to immune checkpoint inhibitor (ICI) therapy and immune dysfunction.
  • Significant differences in genome copy numbers and drug sensitivity were observed among the subtypes.
  • The developed prognostic risk model showed promising predictive performance.
  • Upregulated SHC1 expression correlated with poorer immunotherapy response and shorter survival in ccRCC patients.

Conclusions:

  • Targeting IGF regulators presents a potential therapeutic strategy across multiple cancers.
  • IGF regulator signatures can modulate the tumor immune microenvironment through immune program activation.
  • Inhibition of SHC1 may enhance immunotherapy efficacy and positions SHC1 as a viable therapeutic target for ccRCC.
Keywords:
IGFSHC1clear cell renal cell carcinomamolecular subtypesmulti-omicstumor immunity

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