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DNAH7 mutations benefit colorectal cancer patients receiving immune checkpoint inhibitors
Wenjuan Yang1,2, Zhengjie Shen3, Ti Yang4
1The First Clinical Medical College of Nanjing University of Chinese Medicine, Nanjing, China.
Background:
Colorectal cancer (CRC) is a malignant tumor associated with a high mortality rate. While the advent of immune checkpoint inhibitors (ICIs) has been a gamechanger, only a small percentage of CRC patients benefit from ICIs. The pathological mechanism of CRC is not well understood, but somatic mutations, especially missense mutations, are believed to play an important role. This study examined the relationship between ICIs in colorectal cancer and missense mutations in the axonemal dynein heavy chain gene 7 (DNAH7).
Methods:
A clinical cohort (n=690) and the CRC data from the publicly available Cancer Genome Atlas (TCGA) were examined. Gene Set Enrichment Analysis, ESTIMATE analysis, and clinical correlation analysis were performed to explore the effects and mechanisms of DNAH7 mutation on immunotherapy in colorectal cancer.
Results:
The results showed that CRC patients with DNAH7 mutations can benefit more from ICIs (P<0.05). Patients with DNAH7 mutation had higher ESTIMATE scores, immune scores, and matrix scores, compared to patients without the DNAH7 mutation (P<0.001). The transport of small molecules, keratinization, asthma, autoimmune thyroid disease, allograft rejection, and other pathways were significantly enriched in DNAH7 mutated tissues (P<0.05). The top key genes associated with the DNAH7 mutation included AQP8, MS4A12, GUCA2B, and ZG16 (P<0.01).
Conclusions:
The current study not only demonstrated the significance of DNAH7 as a risk factor and prognostic feature in CRC, but also revealed that DNAH7 mutations might affect the clinical efficacy of ICIs by impacting the tumor immune microenvironment.
Insights
Colorectal cancer patients with axonemal dynein heavy chain gene 7 (DNAH7) mutations may respond better to immune checkpoint inhibitors (ICIs). DNAH7 mutations are linked to improved immunotherapy outcomes by influencing the tumor microenvironment.
Area of Science:
- Oncology
- Immunotherapy
- Genetics
Background:
- Colorectal cancer (CRC) presents a high mortality rate, with limited patient benefit from immune checkpoint inhibitors (ICIs).
- Somatic mutations, particularly missense mutations, are implicated in CRC pathogenesis, yet their precise role remains unclear.
- Understanding the molecular drivers of CRC is crucial for improving treatment efficacy.
Purpose of the Study:
- To investigate the association between missense mutations in the axonemal dynein heavy chain gene 7 (DNAH7) and the response to ICIs in colorectal cancer.
- To explore the potential mechanisms by which DNAH7 mutations influence the tumor immune microenvironment and immunotherapy outcomes.
Main Methods:
- Analysis of a clinical cohort (n=690) and The Cancer Genome Atlas (TCGA) CRC data.
- Application of Gene Set Enrichment Analysis (GSEA), ESTIMATE analysis, and clinical correlation analysis.
- Examination of the impact of DNAH7 mutations on immune cell infiltration and stromal/immune scores.
Main Results:
- CRC patients with DNAH7 mutations demonstrated significantly improved benefit from ICIs (P<0.05).
- DNAH7-mutated tissues exhibited higher ESTIMATE, immune, and matrix scores (P<0.001).
- Enriched pathways in DNAH7-mutated tissues included small molecule transport, keratinization, and immune-related processes; key associated genes were AQP8, MS4A12, GUCA2B, and ZG16 (P<0.01).
Conclusions:
- DNAH7 mutations serve as a significant risk factor and prognostic indicator in colorectal cancer.
- DNAH7 mutations may enhance the clinical efficacy of ICIs by modulating the tumor immune microenvironment.
- Targeting DNAH7 could represent a novel therapeutic strategy for improving CRC immunotherapy outcomes.
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