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Published on: March 14, 2019
Identification of DNA Repair-related Genes as Biomarkers Reflecting MSI, TMB, and TIL in Colorectal Cancer
Junya Fukuda1, Tomoya Sudo2, Maako Kikuchi3
1Department of Surgery, Kurume University School of Medicine, Kurume, Japan; fukuda_junya@kurume-u.ac.jp.
Background/Aim:
There are no established biomarkers for immune checkpoint inhibitors (ICI) in colorectal cancer (CRC) with microsatellite stability (MSS) or proficient mismatch repair (pMMR). Therefore, this study aimed to identify biomarkers for ICI benefit in patients with pMMR by analyzing the down-regulated DNA repair-related genes involved in highly immunogenic and immune responses, and comparing their expression levels and clinical features.
Materials And Methods:
Mismatch repair (MMR), tumor-infiltrating lymphocytes (TIL), and tumor mutation burden (TMB) were evaluated in 13 CRC cases and mRNA expression levels of 95 DNA repair-related genes were measured. DNA repair-related genes with reduced mRNA expression in the high immunogenicity and high immune response groups were identified. Then, the mRNA expression levels of the identified DNA repair-related genes were measured in 135 patients with CRC. Hierarchical cluster analysis was performed using the mRNA expression levels to compare the clinicopathological characteristics of each cluster.
Results:
ATR, LIG4, and RAD52 mRNA levels were significantly down-regulated in the high immunogenicity group. GADD45B, SMUG1, and XRCC6 mRNA levels were significantly down-regulated in the high immune response group. Cases in the cluster with reduced mRNA expression of the six genes were pMMR cases. CD8 mRNA expression level was higher in this cluster than in the other clusters.
Conclusion:
Decreased mRNA expression levels of ATR, LIG4, RAD52, GADD45B, SMUG1, and XRCC6 genes were associated with high cytotoxic T cell and TMB levels, suggesting that these genes could serve as biomarkers for ICI efficacy in pMMR cases.
Insights
Biomarkers for immune checkpoint inhibitors (ICI) in colorectal cancer (CRC) with proficient mismatch repair (pMMR) are lacking. Six DNA repair genes (ATR, LIG4, RAD52, GADD45B, SMUG1, XRCC6) show decreased expression and may predict ICI benefit in pMMR CRC.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- No established biomarkers exist for immune checkpoint inhibitor (ICI) efficacy in microsatellite stable (MSS) or proficient mismatch repair (pMMR) colorectal cancer (CRC).
- Identifying predictive biomarkers is crucial for optimizing ICI treatment in this patient population.
Purpose of the Study:
- To identify novel biomarkers for ICI benefit in pMMR CRC.
- To analyze down-regulated DNA repair-related genes associated with high immunogenicity and immune responses.
Main Methods:
- Evaluated mismatch repair (MMR), tumor-infiltrating lymphocytes (TIL), and tumor mutation burden (TMB) in 13 CRC cases.
- Measured mRNA expression of 95 DNA repair genes, identifying those with reduced expression in high immunogenicity/immune response groups.
- Analyzed expression of six identified genes in 135 pMMR CRC patients using hierarchical cluster analysis.
Main Results:
- ATR, LIG4, RAD52 mRNA levels were significantly down-regulated in the high immunogenicity group.
- GADD45B, SMUG1, XRCC6 mRNA levels were significantly down-regulated in the high immune response group.
- A cluster with reduced expression of these six genes comprised pMMR cases and showed higher CD8 mRNA expression.
Conclusions:
- Decreased mRNA expression of ATR, LIG4, RAD52, GADD45B, SMUG1, and XRCC6 is linked to high cytotoxic T cell and TMB levels.
- These six genes may serve as predictive biomarkers for ICI efficacy in pMMR CRC patients.
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