Distinct Hypoxia-Related Gene Profiling Characterizes Clinicopathological Features and Immune Status of Mismatch Repair-Deficient Colon Cancer

Xu, Yixin; Hu, Junjie; Cao, Can; Zhang, Mili; Liu, You Dong; Chen, Haonan; Wei, Shanshan; Zhu, Zuo-Nong; Yang, Yuqin; Yu, Liang; Li, Jikun

doi:10.1155/2021/2427427

Cited by 4 publications

(2 citation statements)

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“…HALLMARK_HYPOXIA: This gene signature contained 200 genes and could be searched in GSEA database (http://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_HYPOXIA.html) [11]. It has been identi ed to be related to the clinicopathological features and immune status of colorectal cancer in our previous studies [12,13].…”

Section: Construction Of the Multiple Gene Signatures Listmentioning

confidence: 99%

Functional Gene Signature Offers a Powerful Tool for Characterizing Clinicopathological Features and Depicting Tumor Immune Microenvironment of Colorectal Cancer

Zhu,

Li,

et al. 2024

Preprint

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Background: Colorectal cancer, a prevalent malignancy worldwide, poses a significant challenge due to the lack of effective prognostic tools. In this study, we aimed to develop a functional gene signature to stratify colorectal cancer patients into different groups with distinct characteristics, which will greatly facilitate disease prediction. Results: Patients could be stratified into high- and low-risk groups using the prediction model built based on the functional gene signature. This innovative approach not only predicts clinicopathological features but also reveals the tumor immune microenvironment types and responses to immunotherapy. The study reveals that patients in the high-risk group exhibit poorer pathological features, including invasion depth, lymph node metastasis, and distant metastasis, as well as unfavorable survival outcomes in terms of overall survival and disease-free survival. The underlying mechanisms for these observations are attributed to upregulated tumor-related signaling pathways, increased infiltration of pro-tumor immune cells, decreased infiltration of anti-tumor immune cells, and a lower tumor mutation burden. Consequently, patients in the high-risk group exhibit a diminished response to immunotherapy. Furthermore, the high-risk group demonstrates enrichment in extracellular matrix-related functions and significant infiltration of cancer-associated fibroblasts (CAFs). Single-cell transcriptional data analysis identifies CAFs as the primary cellular type expressing hub genes, namely ACTA2, TPM2, MYL9, and TAGLN. This finding is further validated through multiple approaches, including mIHC (multiplex immunohistochemistry), PCR (polymerase chain reaction), and western blot analysis. Notably, TPM2 emerges as a potential biomarker for identifying CAFs in colorectal cancer, distinguishing them from both colorectal cancer cell lines and normal colon epithelial cell lines. Co-culture of CAFs and colorectal cancer cells identified that CAFs could enhance the tumorigenic biofunctions of cancer cells indirectly, which could be partially inhibited by knocking down CAF original TPM2 expression. Conclusions: This study introduces a functional gene signature that effectively and reliably predicts clinicopathological features and the tumor immune microenvironment in colorectal cancer. Moreover, the identification of TPM2 as a potential biomarker for CAFs holds promising implications for future research and clinical applications in the field of colorectal cancer.

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Section: Construction Of the Multiple Gene Signatures Listmentioning

confidence: 99%

Functional Gene Signature Offers a Powerful Tool for Characterizing Clinicopathological Features and Depicting Tumor Immune Microenvironment of Colorectal Cancer

Zhu,

Li,

et al. 2024

Preprint

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“…Transcriptomic profiling of MSI-H/dMMR gastrointestinal tumors showed that hypoxia-related signaling pathways were upregulated in ICI nonresponders ( 76 ). Recently, several studies proposed that hypoxia-related genes can be classified as predicting immune cell infiltration and prognosis of colon cancer patients ( 25 , 28 , 150 ). These genes provide potential therapeutic targets for immunotherapy as well as prognostic biomarkers for colon cancer patients.…”

Section: Other Gene Signatures Of the Tme As Predictive Biomarkers Fo...mentioning

confidence: 99%

Predictive biomarkers of colon cancer immunotherapy: Present and future

Hou

Zhu

2022

Front. Immunol.

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Immunotherapy has revolutionized colon cancer treatment. Immune checkpoint inhibitors (ICIs) have shown clinical benefits for colon cancer patients, especially those with high microsatellite instability (MSI-H). In 2020, the US Food and Drug Administration (FDA)-approved ICI pembrolizumab as the first-line treatment for metastatic MSI-H colon cancer patients. Additionally, neoadjuvant immunotherapy has presented efficacy in treating early-stage colon cancer patients. Although MSI has been thought of as an effective predictive biomarker for colon cancer immunotherapy, only a small proportion of colon cancer patients were MSI-H, and certain colon cancer patients with MSI-H presented intrinsic or acquired resistance to immunotherapy. Thus, further search for predictive biomarkers to stratify patients is meaningful in colon cancer immunotherapy. Except for MSI, other biomarkers, such as PD-L1 expression level, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), certain gut microbiota, ctDNA, and circulating immune cells were also proposed to be correlated with patient survival and ICI efficacy in some colon cancer clinical studies. Moreover, developing new diagnostic techniques helps identify accurate predictive biomarkers for colon cancer immunotherapy. In this review, we outline the reported predictive biomarkers in colon cancer immunotherapy and further discuss the prospects of technological changes for biomarker development in colon cancer immunotherapy.

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