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Updated: Jun 12, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Relationship among DDR gene mutations, TMB and PD-L1 in solid tumour genomes identified using clinically actionable
Danyi Wang1, Brian Elenbaas2, Karthikeyan Murugesan3
1Clinical Measurements Sciences, Global Research & Development, EMD Serono Research & Development Institute, Inc., an affiliate of Merck KGaA, Billerica, MA, USA.
Abstract:
The DNA damage response (DDR) pathway regulates DNA repair and cell survival, and inactivating mutations in DDR genes can increase tumour mutational burden (TMB), a predictive biomarker of treatment benefit from anti-PD-1/PD-L1 immunotherapies. However, a better understanding of the relationship among specific DDR mutations, TMB and PD-L1 expression is needed to improve translational strategies. Here, we determined genomic alteration frequencies in selected DDR genes that are clinically actionable biomarkers and investigated their association with TMB and PD-L1 in bladder, colorectal, non-small cell lung, ovarian and prostate cancers using the FoundationInsights® web portal. Our results not only confirm known associations, such as mismatch repair and POLE gene mutations with high TMB, but also identify significant associations between mutations in the SWI/SNF chromatin remodelling genes ARID1A and SMARCA4 and high TMB in multiple tumour types. Mutations in the ATR gene were associated with high TMB in colorectal and prostate cancers; however, associations between individual DDR mutations and high PD-L1 expression were uncommon and tumour-type specific. Finally, we found that high TMB and high PD-L1 expression were poorly associated, emphasising their independence as predictive biomarkers for immune checkpoint inhibitor use.
Insights
Specific DNA damage response (DDR) gene mutations, like those in SWI/SNF genes, are linked to higher tumor mutational burden (TMB). However, DDR mutations rarely correlate with PD-L1 expression, highlighting their independent roles in immunotherapy.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- The DNA damage response (DDR) pathway is crucial for DNA repair and cell survival.
- Inactivating mutations in DDR genes can elevate tumor mutational burden (TMB), a biomarker for anti-PD-1/PD-L1 immunotherapy efficacy.
- Understanding the interplay between DDR mutations, TMB, and PD-L1 expression is vital for optimizing cancer treatment strategies.
Purpose of the Study:
- To determine the frequencies of genomic alterations in clinically actionable DDR genes.
- To investigate the associations between DDR gene mutations, TMB, and PD-L1 expression across various cancer types.
- To clarify the relationship between TMB and PD-L1 expression as predictive biomarkers for immunotherapy.
Main Methods:
- Utilized the FoundationInsights® web portal for genomic data analysis.
- Analyzed mutation frequencies in selected DDR genes (e.g., mismatch repair, POLE, SWI/SNF, ATR).
- Assessed associations between DDR mutations, TMB levels, and PD-L1 expression in bladder, colorectal, non-small cell lung, ovarian, and prostate cancers.
Main Results:
- Confirmed known associations between mismatch repair and POLE mutations with high TMB.
- Identified significant links between SWI/SNF gene mutations (ARID1A, SMARCA4) and high TMB in multiple cancer types.
- Found ATR mutations associated with high TMB in colorectal and prostate cancers.
- Observed that associations between individual DDR mutations and high PD-L1 expression were infrequent and cancer-specific.
- Demonstrated a weak correlation between high TMB and high PD-L1 expression, indicating their distinct roles.
Conclusions:
- Specific DDR gene mutations, particularly in SWI/SNF and ATR, are associated with increased TMB in various cancers.
- Individual DDR mutations have limited predictive value for PD-L1 expression.
- High TMB and high PD-L1 expression are largely independent biomarkers for predicting response to immune checkpoint inhibitors.
