New Study Identifies Recurrently-Mutated Genes and Pathways Associated with Cancer Immunotherapy Response

Strategic Insights -

Research from the New York Genome Center has identified several genes and pathways that predict the response to immune checkpoint blockade (ICB) therapy in cancer patients. The study analyzed six whole-exome sequencing cohorts with matched disease outcomes to identify genes and pathways that are significantly mutated and associated with ICB response. The researchers developed a classifier, called Cancer Immunotherapy Response CLassifiEr (CIRCLE), which outperformed tumor mutational burden alone in predicting ICB response with a 10.5% increase in sensitivity and an 11% increase in specificity.

Key Takeaways:

  • The study identified four genes (BCLAF1, KRAS, BRAF, and TP53) and three pathways (MAPK signaling, p53 associated, and immunomodulatory) as predictors of ICB response.
  • The Cancer Immunotherapy Response CLassifiEr (CIRCLE) classifier was developed to predict ICB response and showed improved performance compared to tumor mutational burden alone.
  • CIRCLE outperformed tumor mutational burden alone with a 10.5% increase in sensitivity and an 11% increase in specificity.
  • The study focused on genes and pathways that are significantly mutated after correction for epigenetic, replication timing, and sequence-based covariates.
  • The researchers envision that CIRCLE and the analysis of recurrently mutated cancer genes will pave the way for better prognostic tools for cancer immunotherapy.

Statistics:

  • 10.5% increase in sensitivity of CIRCLE compared to tumor mutational burden alone
  • 11% increase in specificity of CIRCLE compared to tumor mutational burden alone
  • 4 genes (BCLAF1, KRAS, BRAF, and TP53) identified as predictors of ICB response
  • 3 pathways (MAPK signaling, p53 associated, and immunomodulatory) identified as predictors of ICB response
  • 6 whole-exome sequencing cohorts analyzed with matched disease outcomes

Sources:

  • Recurrent Somatic Mutations As Predictors of Immunotherapy Response. Nature Communications, 2022;13(1).
  • Nature Portfolio, Heidelberger Platz 3, Berlin, 14197, Germany.
  • The New York Genome Center, New York, NY 10013, United States.
  • U.S. Department of Health & Human Services | National Institutes of Health, U.S. Department of Health & Human Services | NIH | National Cancer Institute.