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Published on: February 8, 2018
Establishment of a novel gene panel as a biomarker of immune checkpoint inhibitor response
Yi-Ru Pan1, Chiao-En Wu2, Yu-Chao Wang3,4
1Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch Chang Gung University Taoyuan Taiwan.
Objective:
Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although the predictive tool is still unknown.
Methods:
This study aimed to develop a novel gene panel by selecting DNA damage response (DDR) genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) databank and validating them in previously reported cohorts. This association between DDR gene mutations and tumor mutation burden or microsatellite status was analysed from The Cancer Genome Atlas (TCGA) databank. Furthermore, we made the gene panel clinically accessible and predicted the response in clinical patients receiving ICIs by using cell-free DNA.
Results:
The top 20 mutated DDR genes in various cancers (total 37 genes) were taken from the COSMIC databank, and the DDR genes found to individually predict a response rate > 50% in Van Allen's cohort were selected (Science, 350, 2015 and 207). Eighteen DDR genes were selected as the gene panel. The prevalence and predicted response rate were validated in the other three reported cohorts. Tumor mutational burden-high was positively associated with mutations of the 18 DDR genes for most cancers. We used cell-free DNA to test the DDR gene panel and validated by our patients receiving ICIs. This DDR gene panel accounted for approximately 30% of various cancers, achieving a predicted response rate of approximately 60% in patients with a mutated gene panel receiving ICIs.
Conclusion:
This gene panel is a novel and reliable tool for predicting the response to ICIs in cancer patients and guides the appropriate administration of ICIs in clinical practice.
Insights
A novel DNA damage response (DDR) gene panel predicts response to immune checkpoint inhibitors (ICIs) in various cancers. This tool, utilizing cell-free DNA, identifies patients likely to benefit from ICI therapy, improving clinical practice.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Immune checkpoint inhibitors (ICIs) are standard cancer care.
- Predictive biomarkers for ICI response remain largely unknown.
- Identifying patients who will benefit from ICIs is crucial for effective treatment.
Purpose of the Study:
- To develop a novel gene panel for predicting ICI response.
- To select DNA damage response (DDR) genes using COSMIC and TCGA databanks.
- To validate the panel's clinical utility using cell-free DNA (cfDNA).
Main Methods:
- Selected top 20 mutated DDR genes from COSMIC databank.
- Identified 18 DDR genes predicting >50% response rate in a known cohort.
- Validated the gene panel in independent cohorts and cfDNA samples.
Main Results:
- An 18-gene DDR panel was established.
- Mutations in these DDR genes positively correlated with tumor mutational burden.
- The panel predicted a ~60% response rate in patients receiving ICIs, applicable to ~30% of cancers.
Conclusions:
- The developed DDR gene panel is a reliable predictor of ICI response.
- This tool can guide the clinical application of ICIs.
- It offers a novel approach to personalize cancer immunotherapy.
