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A Networks-Based Approach Identifies DDR Genes Not Associated With TMB Yet Predictive of Immune Checkpoint Response

37 Pages Posted: 28 Jun 2021 Publication Status: Published

See all articles by William Weir

William Weir

University of North Carolina, Chapel Hill - Curriculum in Bioinformatics & Computational Biology

Peter J. Mucha

University of North Carolina, Chapel Hill - Curriculum in Bioinformatics & Computational Biology; Dartmouth College - Department of Mathematics

William Kim

University of North Carolina (UNC) at Chapel Hill - Lineberger Comprehensive Cancer Center

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Abstract

Immune checkpoint blockade (ICB) therapies have 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 novel, networks-based test and Network Based-Expected TMB Score (N-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 are nevertheless predictive of ICB benefit in two separate studies, demonstrating that their inactivation contributes to ICB response in a TMB independent manner.

Suggested Citation

Weir, William and Mucha, Peter J. and Mucha, Peter J. and Kim, William, A Networks-Based Approach Identifies DDR Genes Not Associated With TMB Yet Predictive of Immune Checkpoint Response. Available at SSRN: https://ssrn.com/abstract=3875772 or http://dx.doi.org/10.2139/ssrn.3875772
This version of the paper has not been formally peer reviewed.

William Weir

University of North Carolina, Chapel Hill - Curriculum in Bioinformatics & Computational Biology ( email )

102 Ridge Road
Chapel Hill, NC NC 27514
United States

Peter J. Mucha

University of North Carolina, Chapel Hill - Curriculum in Bioinformatics & Computational Biology ( email )

102 Ridge Road
Chapel Hill, NC NC 27514
United States

Dartmouth College - Department of Mathematics ( email )

United States

William Kim (Contact Author)

University of North Carolina (UNC) at Chapel Hill - Lineberger Comprehensive Cancer Center ( email )

102 Ridge Road
Chapel Hill, NC 27514
United States

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