Evaluation of 30 DNA damage response and 6 mismatch repair gene mutations as biomarkers for immunotherapy outcomes across multiple solid tumor types

Abstract

Objective: DNA damage response (DDR) genes have low mutation rates, which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor (ICI) treatment. Thus, a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy. Methods: A total of 39,631 patients with mutation data were selected from the cBioPortal database. A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center (FUSCC). A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis. A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute (DFCI) cohort were obtained from a published dataset. The Cancer Genome Atlas (TCGA) level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal. Results: Six MMR and 30 DDR genes were included in this study. Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI, and most of them predicted the therapeutic efficacy of ICI, in a manner dependent on TMB, except for 4 combined DDR gene mutations, which were associated with the therapeutic efficacy of ICI independently of the TMB. Single MMR/ DDR genes showed low mutation rates; however, the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high, reaching 10%-30% in several cancer types. Conclusions: Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy. KEYWORDSImmune checkpoint inhibitor therapy; prediction of efficacy; tumor mutation burden; mismatch repair deficiency; DNA damage response genes

The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy

“…However, the use of individual DDR pathway changes in guiding ICIs treatment remains to be explored [ 20 , 47 , 69 ]. Researchers have established reliable DDR scoring models and effectively analyzed the predictive effect of co-mutation, the DDR gene models of various researchers can effectively predict specific response to ICIs treatment [ 69 – 72 ]. In one case, Yi-Ru Pan et al selected 18 DDR genes as the defined gene panel and achieved a predicted response rate of about 60% in patients with DDR mutations [ 73 ].…”

“…A high TMB can predict MSI-H and vice versa [ 64 , 69 , 151 ]. It should be noted that although MSI-H/dMMR is associated with TMB-H, DDR genes are still associated with a high TMB after MSI-H/dMMR is excluded [ 69 ].…”

“…A high TMB can predict MSI-H and vice versa [ 64 , 69 , 151 ]. It should be noted that although MSI-H/dMMR is associated with TMB-H, DDR genes are still associated with a high TMB after MSI-H/dMMR is excluded [ 69 ]. As for the relationship between NAL and TMB, previous studies have proven that high TMB can cause an increase in neoantigens [ 137 ].…”

“…Specifically, an increased mutation load enhances CD8 + T cell infiltration (Fig. 1 ) [ 69 , 101 , 144 ], and the intracellular accumulation of DNA fragments furthers induces innate and adaptive immune activation [ 78 ]. An increase of NAL can also lead to active immune stimulation of the TME.…”

Targeting DNA Damage Response and Immune Checkpoint for Anticancer Therapy

“…As described above, only a subgroup of patients with specific genetic contexts (dMMR/MSI-H) have a better response rate to ICB therapy [ 101 , 102 ]. Thus, DDR alterations are useful biomarkers for choosing the patients to receive ICB therapy [ 106 , 107 ]. Alternatively, targeting DDR mechanisms through the use of PARP and other DDR inhibitors is also a promising way to induce a “hot” TIME to improve the efficacy of cancer immunotherapy.…”