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Updated: Sep 22, 2025
Author Spotlight: Unlocking Insights into the Immune Cell Landscape of Tumors
Published on: August 18, 2023
A bipartite graph-based expected networks approach identifies DDR genes not associated with TMB yet predictive of
William H Weir1, Peter J Mucha2, William Y Kim3
1Curriculum in Bioinformatics & Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract:
Immune checkpoint blockade (ICB) has had remarkable success for treatment of solid tumors. However, as only a subset of patients exhibit responses, there is a continued need for biomarker development. Numerous reports have shown a link between tumor mutational burden (TMB) and ICB response, while others have identified a link between ICB response and mutation in DNA damage repair (DDR) genes. However, it remains unclear to what extent mutations in DDR genes hold predictive value above and beyond their association with TMB. Herein, we present a networks-based test and bipartite graph-based expected TMB score (BiG-BETS) with higher specificity for discriminating DDR genes and pathways that are associated with elevated TMB. Moreover, we find that mutations in certain DDR genes that are not associated with elevated TMB (low BiG-BETS) are nevertheless predictive of ICB benefit in high TMB patients, demonstrating that their inactivation contributes to ICB response in a TMB-independent manner.
Insights
Immune checkpoint blockade (ICB) shows promise for solid tumors, but patient response varies. This study identifies specific DNA damage repair (DDR) gene mutations that predict ICB benefit, even independently of tumor mutational burden (TMB).
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Immune checkpoint blockade (ICB) therapy is effective against solid tumors, but response rates are limited.
- Tumor mutational burden (TMB) and DNA damage repair (DDR) gene mutations are associated with ICB response.
- The independent predictive value of DDR mutations beyond TMB for ICB response remains unclear.
Purpose of the Study:
- To develop a method to specifically identify DDR genes and pathways associated with elevated TMB.
- To investigate whether DDR gene mutations predict ICB response independently of TMB.
Main Methods:
- Development of a networks-based test and a bipartite graph-based expected TMB score (BiG-BETS).
- Utilizing BiG-BETS to assess the association between DDR genes/pathways and TMB.
- Evaluating the predictive value of DDR mutations for ICB benefit in relation to TMB levels.
Main Results:
- The BiG-BETS score effectively discriminates DDR genes and pathways linked to high TMB.
- Mutations in specific DDR genes (low BiG-BETS) predict ICB benefit in patients with high TMB.
- These DDR mutations contribute to ICB response in a manner independent of TMB.
Conclusions:
- BiG-BETS enhances the specificity of identifying TMB-associated DDR alterations.
- Certain DDR gene mutations offer predictive value for ICB response beyond TMB.
- Targeting these TMB-independent DDR alterations may improve immunotherapy strategies.
