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Pan-cancer analysis of ARID1A Alterations as Biomarkers for Immunotherapy Outcomes.

ABSTRACT: ARID1A alterations would compromise mismatch repair pathway and increase the number of tumor-infiltrating lymphocytes and PD-L1 expression in some cancers, which would cooperate with immune checkpoint inhibitors (ICIs) treatment. However, a comprehensive analysis of ARID1A alteration frequency and its predictive value for ICI treatment outcome in cancers has not yet been investigated. Hence, we performed this pan-cancer analysis to evaluate the prevalence and predictive value of ARID1A alterations across >40,000 cases in multiple cancer types. We found a high frequency (6.2%) of ARID1A, which were associated with significantly higher tumor mutation burden level across various cancers. Importantly, patients with ARID1A alterations and advanced cancers had the substantially prolonged overall survival in ICI treatment cohort, suggesting it might be used to predict a survival benefit from ICI therapy across multiple cancer types. Notably, ARID1A alterations were correlated with markedly high immune infiltrates in endometrial, stomach and colon cancer. However, patients with ARID1A-mutant renal clear cell carcinoma had dramatically lower CD8+ T cell infiltrations than those without, indicating the association between ARID1A alterations and immune infiltrates was cancer-dependent. Collectively, our findings highlight the important value of ARID1A alterations as pan-cancer predictive biomarkers for ICI treatment.

SUBMITTER: Jiang T

PROVIDER: S-EPMC6959029 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pan-cancer analysis of ARID1A Alterations as Biomarkers for Immunotherapy Outcomes.

Jiang Tao T Chen Xiaoxia X Su Chunxia C Ren Shengxiang S Zhou Caicun C

Journal of Cancer 20200101 4

ARID1A alterations would compromise mismatch repair pathway and increase the number of tumor-infiltrating lymphocytes and PD-L1 expression in some cancers, which would cooperate with immune checkpoint inhibitors (ICIs) treatment. However, a comprehensive analysis of ARID1A alteration frequency and its predictive value for ICI treatment outcome in cancers has not yet been investigated. Hence, we performed this pan-cancer analysis to evaluate the prevalence and predictive value of <i ...[more]

PMID: 31949479

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Project description:AimInsulin-like growth factor-1 receptor (IGF-1R) is one of the main members of the tyrosine protein kinase receptor family. This receptor binds insulin-like growth factor-1 (IGF-1) with a high affinity. IGF-1 is a member of a family of proteins involved in mediating growth and development. However, the correlations of IGF-1 and IGF-1R to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear.MethodThis research comprehensively analyzed the expression pattern of IGF-1 and IGF-1R and the influence of IGF-1 and IGF-1R on clinical significance in prognosis prediction among 33 types of malignancies using The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) databases. The correlation between IGF-1, IGF-1R, and cancer immunity was explored.ResultsIGF-1 and IGF-1R displayed inconsistent gene expression levels among diverse cancer cell lines. Typically, high expression level of IGF-1 and IGF-1R was detected in most malignant tumors. High expression of IGF-1 was closely bound up with the unfavorable overall survival (OS) for patients in BLCA, CHOL, and LAML upon Cox and Kaplan-Meier analyses. While high expression of IGF-1R was closely bound up with the unfavorable overall survival (OS) for patients in BLCA, LIHC, and LUAD. Furthermore, high expression level of IGF-1 and IGF-1R were closely connected with high degrees of tumor infiltrates, including CD4+ T cell, dendritic cells, and macrophages. In addition, we found that IGF-1 was commonly positively correlated with the expression of gene markers including LAIR1, ICOS, CD40LG, CTLA4, CD48, CD28, CD200R1, HAVCR2, and CD86. Whereas, IGF-1R was commonly positively correlated with the expression of gene markers including NRP1 and CD276. More importantly, IGF-1 and IGF-1R expression were correlated with tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) of different types of cancers.ConclusionsThe impact of high IGF-1 and IGF-1R on prognosis and immune infiltrates differs across cancer types. Anti-IGF-1R therapy may inhibit tumor growth and contribute to immunotherapy in LIHC and KIRC.

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Pan-cancer analysis of ARID1A Alterations as Biomarkers for Immunotherapy Outcomes.

Publications

Pan-cancer analysis of <i>ARID1A</i> Alterations as Biomarkers for Immunotherapy Outcomes.

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