Dataset Information

CARD11 alteration as a candidate biomarker of skin cutaneous melanoma treated with immune checkpoint blockade.

ABSTRACT:

Background

Immune checkpoint inhibitors (ICIs) can be problematic, including a lack of sustained clinical response, in the treatment of skin cutaneous melanoma (SKCM) patients; therefore, predictive biomarkers are urgently needed. Recently, gene mutations identified by melanoma genomic analysis have shown great predictive potential.

Methods

We collected an immunotherapy cohort and The Cancer Genome Atlas (TCGA)-SKCM cohort from published studies and tested the predictive function of the CARD11 mutation. We then further studied the association between the CARD11 mutation and tumor immunogenicity by studying related genes and pathways in the tumor microenvironment (TME).

Results

In the immunotherapy and TCGA-SKCM cohorts, patients with CARD11-mutant (MT) tumors had longer overall survival (OS) and a better prognosis than those with CARD11-wild-type (WT) tumors. CARD11-MT tumors had higher immunogenicity, and gene expression related to immunosuppression was significantly downregulated in CARD11-MT tumors. We found that immunosuppression-related pathways were significantly downregulated in CARD11-MT tumors, while immune activation-related pathways were significantly upregulated. Additionally, CARD11-MT tumors had more DNA damage response and repair (DDR) pathway mutations.

Conclusions

CARD11 mutation is associated with longer OS and a better prognosis after ICI treatment. Therefore, the CARD11 gene can be used as a biomarker for predicting the efficacy of ICIs in SKCM patients.

SUBMITTER: Si Y

PROVIDER: S-EPMC7847528 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

CARD11 alteration as a candidate biomarker of skin cutaneous melanoma treated with immune checkpoint blockade.

Si Yutian Y Lin Anqi A Ding Weimin W Meng Hui H Luo Peng P Zhang Jian J

American journal of translational research 20210115 1

<h4>Background</h4>Immune checkpoint inhibitors (ICIs) can be problematic, including a lack of sustained clinical response, in the treatment of skin cutaneous melanoma (SKCM) patients; therefore, predictive biomarkers are urgently needed. Recently, gene mutations identified by melanoma genomic analysis have shown great predictive potential.<h4>Methods</h4>We collected an immunotherapy cohort and The Cancer Genome Atlas (TCGA)-SKCM cohort from published studies and tested the predictive function ...[more]

PMID: 33527024

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Project description:BackgroundImmune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking.MethodsClinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset.ResultsAmong twenty-one key genes involving in the regulation of DNA methylation, TET1-mutant (TET1-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (p=0.003). TET1 was recurrently mutated across multiple cancers and more frequently seen in skin, lung, gastrointestinal, and urogenital cancers. In the discovery cohort (n = 519), significant differences were observed between TET1-MUT and TET1-wildtype (TET1-WT) patients regarding objective response rate (ORR, 60.9% versus 22.8%, P < 0.001), durable clinical benefit (DCB, 71.4% versus 31.6%, P < 0.001), and progression-free survival (PFS, hazard ratio = 0.46 [95% confidence interval, 0.25 to 0.82], P = 0.008). In the validation cohort (n = 1395), significant overall survival (OS) benefit was detected in the TET1-MUT patients compared to TET1-WT patients (hazard ratio = 0.47 [95% confidence interval, 0.25 to 0.88], P = 0.019), which was, importantly, independent of tumor mutational burden and high microsatellite instability; as well as not attributed to the prognostic impact of TET1-MUT (P > 0.05 in both two non-ICI-treated cohorts). In TCGA dataset, TET1-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions.ConclusionsTET1-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that TET1-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types.

Project description:BackgroundAs a member of tumor, Skin cutaneous melanoma (SKCM) poses a serious threat to people's health because of its strong malignancy. Unfortunately, effective treatment methods for SKCM remain lacking. FANCI plays a vital role in the occurrence and metastasis of various tumor types. However, its regulatory role in SKCM is unclear. The purpose of this study was to explore the association of FANCI with SKCM.MethodsThis study investigated the expression of FANCI in GSE46517, GSE15605, and GSE114445 from the Gene Expression Omnibus database and The Cancer Genome Atlas (TCGA)-SKCM datasets using the package "limma" or "DESeq2" in R environment and also investigated the prognostic significance of FANCI by utilizing the GEPIA database. Additionally, our research made use of real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemical (IHC) staining to verify FANCI expression between SKCM and normal tissues and developed the knockdown of FANCI in A375 and A875 cells to further analyze the function of FANCI. Finally, this study analyzed the correlation of FANCI and tumor-infiltrating immune cells by CIBERSORT, ESTIMATE, and ssGSEA algorithms.ResultsThe FANCI level was increasing in SKCM tissues from GSE46517, GSE15605, GSE114445, and TCGA-SKCM. However, high FANCI expression correlated with poor overall survival. The RT-qPCR and IHC confirmed the accuracy of bioinformatics. Knocking down FANCI suppresses A375 and A875 cell proliferation, migration, and invasion. FANCI could be involved in the immunological milieu of SKCM by regulating immune responses and infiltrating numerous immune cells, particularly neutrophils, CD8+ T cells, and B cells. Furthermore, patients with SKCM who have a high FANCI expression level are reported to exhibit immunosuppression, whereas those with a low FANCI expression level are more likely to experience positive outcomes from immunotherapy.ConclusionsThe increased FANCI expression in SKCM can be a prognostic biomarker. Knockdown FANCI can reduce the occurrence and progression of SKCM. The FANCI expression provides a foundation for predicting the immune status and treatment of SKCM.

Dataset Information

CARD11 alteration as a candidate biomarker of skin cutaneous melanoma treated with immune checkpoint blockade.

Background

Methods

Results

Conclusions

Publications

CARD11 alteration as a candidate biomarker of skin cutaneous melanoma treated with immune checkpoint blockade.

Similar Datasets

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