Association between PD-L1 variants and PD-L1 expression: A pan-cancer analysis.

e13661 Background: Programmed cell death-1 (PD-L1) expression has become a predictive biomarker of response to immune checkpoint inhibitors (ICIs) in several types of solid tumors. Patients with high expression of PD-L1 can benefit more from immunotherapy. However, whether PD-L1 variants would influence the PD-L1 expression has not been fully studied. Methods: Patients with both mutation and immunohistochemistry results for PD-L1 expression from our dataset was analyzed. Patients with both mutation and RNA expression data were obtained from The Cancer Genome Atlas (TCGA) and also analyzed. Results: In our dataset, 10002 patients were included in the analysis. 101 (1%) patients harbored PD-L1 variants, including 24 with single nucleotide variant (SNV), 1 with fusion, 3 with copy-number reduction, 59 with copy-number gain, and 16 germline SNV. The PD-L1 positive rate was 42% in patients with SNV, 100% in fusion, 0% in copy-number reduction, 78% in copy-number gain, 19% in germline SNV and 39% in patients without PD-L1 variants. 32 studies of 10071 patients from TCGA were included for analysis. 244 (2.22%) patients harboring PD-L1 variants, including 2 with frame shift mutations, 3 with nonsense mutations, 38 with missense mutations, 2 with splices, 3 with fusions, 83 with copy-number reduction and 118 with copy-number amplification. The PD-L1 expression in patients with PD-L1 variants was significantly higher than patients without PD-L1 variants (P < 0.001). Further analysis among PD-L1 variants groups showed that PD-L1 fusion and amplification were associated with higher PD-L1 expression. Conclusions: Our results suggested that the PD-L1 expression was associated with PD-L1 variants. Patients with PD-L1 fusion and copy-number amplification was associated with higher PD-L1 expression, while PD-L1 germline SNV and copy-number deletion was associated with lower PD-L1 expression.Our results suggested that the PD-L1 expression was associated with PD-L1 variants. Patients with PD-L1 fusion and copy-number amplification was associated with higher PD-L1 expression, while PD-L1 germline SNV and copy-number deletion was associated with lower PD-L1 expression.

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Copy number gain of CMTM6 increases the expression of PD-L1 in undifferentiated pleomorphic sarcoma

10.21203/rs.3.rs-201625/v1 ◽

2021 ◽

Author(s):

Shin Ishihara ◽

Takeshi Iwasaki ◽

Kenichi Kohashi ◽

Yuichi Yamada ◽

Yu Toda ◽

...

Keyword(s):

Copy Number ◽

Transmembrane Domain ◽

Gene Copy Number ◽

Copy Number Gain ◽

The Cancer Genome Atlas ◽

Gene Copy ◽

Undifferentiated Pleomorphic Sarcoma ◽

Pleomorphic Sarcoma ◽

Number Variation ◽

Cancer Genome Atlas

Abstract Background Undifferentiated pleomorphic sarcoma (UPS) is a sarcoma with a poor prognosis. A clinical trial, SARC028, revealed that treatment with anti-PD-1 drugs was effective against UPS. Studies have reported that UPS expresses PD-L1, sometime strongly (≥ 50%). However, the mechanism of PD-L1 expression in UPS has remained still unclear. CKLF-like MARVEL transmembrane domain containing 6 (CMTM6) was identified as a novel regulator of PD-L1 expression. The positive relationship between PD-L1 and CMTM6 has been reported in several studies. The aim of this study was to examine CMTM6 expression in UPS and evaluate the relationship between PD-L1 and CMTM6. Materials and methods Fifty-one primary UPS samples were subjected to CMTM6 and PD-L1 immunostaining. CMTM6 expression was assessed using proportion and intensity scores. CMTM6 gene copy number was also evaluated using a real-time PCR-based copy number assay. We also analyzed the mRNA expression and copy number variation of PD-L1 and CMTM6 in The Cancer Genome Atlas (TCGA) data. Results TCGA data indicated that the mRNAs encoded by genes located around 3p22 were coexpressed with CMTM6 mRNA in UPS. Both proportion and intensity scores of CMTM6 positively correlated with strong PD-L1 expression (≥ 50%) (both p = 0.023). CMTM6 copy number gain increased CMTM6 expression. Patients with UPS with a high CMTM6 intensity score had worse prognosis for overall survival. Conclusions CMTM6 expression was significantly correlated with PD-L1 expression. CMTM6 expression induced strong PD-L1 expression (≥ 50%). CMTM6 copy number gain promoted CMTM6 expression and increased PD-L1 expression in UPS.

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Correlation between JAK1/2 expression and immune-related genes and JAK2 gene variants: A pan-cancer analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15057 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15057-e15057

Author(s):

Lichao Xu ◽

Ding Zhang ◽

Guoqiang Wang ◽

Chao Chen ◽

Ying Wang ◽

...

Keyword(s):

Mrna Expression ◽

Copy Number ◽

Checkpoint Inhibitors ◽

The Cancer Genome Atlas ◽

Gene Variants ◽

Missense Mutations ◽

Sequencing Data ◽

Primary Resistance ◽

Immune Related Genes ◽

Pan Cancer

e15057 Background: Loss of function mutations for Janus kinases 1/2 (JAK1/2) have shown to be the underling mechanism of primary resistance to immune checkpoint inhibitors (ICIs). However, the correlation between JAK1/2 expression and immune-related genes have not been studied. Methods: Survival, mRNA expression and whole-exome sequencing data from 32 pan-cancer atlas studies were obtained from The Cancer Genome Atlas (TCGA). Correlations between JAK1/2 expression and immune-related genes were depicted in heatmaps. We also analyzed the association between JAK2 gene variants and JAK2 expression. Results: In total, 10071 samples with mRNA expression data were included for analysis. Expression of 46 immune-related genes were positively correlated with JAK2 expression in 25 tumors instead of JAK1 expression. Patients with higher expression of JAK2 had better prognosis than patients with lower expression of JAK2 in 13 tumors. Among 10071 patients, 363 (3.60%) patients harbored JAK2 variants, including 8 with frame shift mutations, 44 with nonsense mutations, 142 with missense mutations, 11 with splices, 8 with fusions, 90 with copy-number reduction and 116 with copy-number amplification. There was no difference in JAK2 expression between patients with JAK2 variants and those without JAK2 variants. However, JAK2 fusion (2.20%, 8/363) and amplification (31.96%, 116/363) were associated with higher JAK2 expression. Conclusions: Our pan-cancer analysis found that JAK2 expression was correlated with immune-related genes and the prognosis of cancer patients. JAK2 fusion and amplification increased the expression of JAK2. Altogether, patients with high JAK2 expression may benefit from ICIs.

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Multi-Platform Omics Analysis for Identification of Molecular Characteristics and Therapeutic Targets of Uveal Melanoma

Scientific Reports ◽

10.1038/s41598-019-55513-z ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Yong Joon Kim ◽

Seo Jin Park ◽

Kyung Joo Maeng ◽

Sung Chul Lee ◽

Christopher Seungkyu Lee

Keyword(s):

Uveal Melanoma ◽

Copy Number ◽

Checkpoint Inhibitors ◽

Therapeutic Targets ◽

The Cancer Genome Atlas ◽

Molecular Characteristics ◽

Synthetic Lethal ◽

Whole Exome ◽

Cancer Genome Atlas ◽

Sirna Library

AbstractCurrently, there is no effective treatment for metastatic uveal melanoma (UVM). Here, we aimed to identify the mechanism involving intrinsic chemoresistance of metastatic UVM and the relevant therapeutic targets for UVM. We analyzed cohorts of 80 and 67 patients with primary UVM and skin cutaneous melanoma (SKCM), respectively, using The Cancer Genome Atlas dataset. Mutational burdens identified by whole exome sequencing were significantly lower in UVM than in SKCM patients. COSMIC mutational signature analysis identified that most of the mutations in UVM patients (>90%) were associated with spontaneous deamination of 5-methylcytosine or defective mismatch repair. Transcriptome analysis revealed that the MYC signature was more enriched in UVM patients, as compared to SKCM patients. Fifty-nine (73.8%) of 80 UVM patients showed gains in MYC copy number, and a high MYC copy number was associated with aggressive clinicopathological features of tumors and poor survival. Kinome-wide siRNA library screening identified several therapeutic targets, reported as synthetic lethal targets for MYC-addicted cancers. Notably, UVM cell lines showed high susceptibility to a WEE1 inhibitor (MK-1775; adavosertib) at a clinically tolerable dose. Overall, our study identified high MYC activity in UVM, and suggested G2/M checkpoint inhibitors as effective therapeutic targets for UVM.

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Genomic aberration of chromatin regulatory BAF complex as predictive biomarker for immunotherapy in gastrointestinal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4035 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4035-4035

Author(s):

Changsong QI ◽

Sai Ge ◽

Zhi Peng ◽

Xiaotian Zhang ◽

Yu Xu ◽

...

Keyword(s):

Transcriptional Activation ◽

Cancer Cell Line ◽

Predictive Biomarker ◽

The Cancer Genome Atlas ◽

Genomic Aberration ◽

Baf Complex ◽

Mutational Burden ◽

Positive Rate ◽

Cancer Genome Atlas ◽

Immune Related Genes

4035 Background: SNF/SWI, a large ATP-dependent chromatin remodeling complex, is required for transcriptional activation of genes normally repressed by chromatin, and critical to tumor initiation and progression. Here, we analyzed the predictive utility of the mutations of the SNF/SWI members involved in BAF and PBAF complexes, and sought to explore the potential mechanisms. Methods: Clinical, genomic, transcriptional, and immunohistochemical data from immunotherapeutic cohort (MSKCC, n=185), Cancer Cell Line Encyclopedia (CCLE, n=92), The Cancer Genome Atlas (TCGA, n=925), and 3D Medicines database (3DMed, n=1812) were analyzed to explore the predictive effect of genomic aberration of BAF complex on the benefit from immunotherapy in patients with gastrointestinal adenocarcinoma. Results: In the MSKCC cohort involving 185 patients with gastrointestinal adenocarcinoma, the mutation of any member involved in BAF complex ( ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCD1) was significantly associated with prolonged OS of ICI treatment (HR 0.53, 95%CI 0.31-0.90, P=0.019), instead of the mutations of PBAF members including PBRM1 and ARID2. In addition, BAF mutation was not linked with better prognosis in TCGA database, indicating its predictive, not prognostic efficacy of immunotherapy. BAF-mutated samples exhibited higher tumour mutational burden (TMB, P<0.05, Table), and increased mRNA expression of immune-related genes including chemokines and granzyme A. In the 3DMed cohort where tumour samples received both genomic sequencing and PD-L1 immunohistochemical staining, BAF mutation was associated with higher PD-L1 positive rate in tumour cells (P<0.05, Table). Conclusions: Genomic aberration of members in chromatin regulatory BAF complex may serve as a predictive, not prognostic biomarker of ICI benefit in patients with gastrointestinal adenocarcinoma, partially underlying the mechanisms including higher mutational burden, transcription of immune-related genes, and protein-level PD-L1 expression. [Table: see text]

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Somatic copy number alteration predicts clinical benefit of lung adenocarcinoma patients treated with cytokine-induced killer plus chemotherapy

Cancer Gene Therapy ◽

10.1038/s41417-021-00422-5 ◽

2022 ◽

Author(s):

Fan Kou ◽

Lei Wu ◽

Ye Zhu ◽

Baihui Li ◽

Ziqi Huang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

The Cancer Genome Atlas ◽

Whole Exome ◽

Mutation Burden ◽

Cancer Genome Atlas ◽

Nsclc Patients

AbstractSomatic copy number alterations (SCNA), which are widespread in cancer, can predict the efficacy of immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC). However, the usefulness of SCNA for predicting the survival of patients treated with cytokine-induced killer (CIK) cells or chemotherapy (CT) is unknown. This study aimed to explore the correlation between SCNA and clinical outcome in NSCLC patients treated with CIK + CT or CT alone. We performed whole-exome sequencing on 45 NSCLC patients treated with CIK + CT, as well as 305 NSCLC patients treated with CT alone, from The Cancer Genome Atlas, which showed SCNA had a superiority in predicting the progression-free survival (PFS) over tumor mutation burden (TMB) and SCNA + TMB in NSCLC patients treated with CIK + CT, especially in lung adenocarcinoma, while SCNA could not predict the efficacy of CT alone. Additionally, we investigated the association between SCNA and immune cell infiltration by RNA sequencing and immunohistochemistry. The results revealed that SCNA was negatively associated with the expression of dendritic cells. Collectively, this study revealed a negative correlation between SCNA and response to CIK + CT and showed that SCNA is a predictive indicator in LUAD patients treated with CIK + CT.

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LINC00467 Is Upregulated by DNA Copy Number Amplification and Hypomethylation and Shows ceRNA Potential in Lung Adenocarcinoma

Frontiers in Endocrinology ◽

10.3389/fendo.2021.802463 ◽

2022 ◽

Vol 12 ◽

Author(s):

Wen Wang ◽

Hao Bo ◽

Yumei Liang ◽

Guoli Li

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number ◽

Target Genes ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Dna Copy Number ◽

Cerna Network ◽

Cancer Genome Atlas ◽

Copy Number Amplification ◽

Genome Atlas

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. Long noncoding RNAs (lncRNAs) have been implicated in tumorigenesis. LINC00467 is a novel lncRNA that is abnormally expressed in several cancer types including LUAD. However, its function and regulatory mechanism in LUAD progression remain unclear. In this study, based on The Cancer Genome Atlas data mining, we demonstrated that DNA copy number amplification and hypomethylation was positively correlated with LINC00467 expression in LUAD. In addition, DNA copy number amplification was significantly associated with distant metastasis, immune infiltration and poor survival. Microarray analysis demonstrated that LINC00467 knockdown in the LUAD A549 cell line led to a distinct microRNA expression profile that impacted various target genes involved in multiple biological processes. This finding suggests that LINC00467 may regulate LUAD progression by functioning as a competing endogenous RNA (ceRNA). Finally, we constructed a ceRNA network that included two microRNAs (hsa-miR-1225-5p, hsa-miR-575) and five mRNAs (BARX2, BCL9, KCNK1, KIAA1324, TMEM182) specific to LINC00467 in LUAD. Subsequent Kaplan-Meier survival analysis in both The Cancer Genome Atlas and Gene Expression Omnibus databases revealed that two genes, BARX2 and BCL9, were potential prognostic biomarkers for LUAD patients. In conclusion, our data provide possible mechanisms underlying the abnormal upregulation of LINC00467 as well as a comprehensive view of the LINC00467-mediated ceRNA network in LUAD, thereby highlighting its potential role in diagnosis and therapy.

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A comprehensive analysis of the angiogenesis-related genes in glioblastoma multiforme vs. brain lower grade glioma

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20190131 ◽

2020 ◽

Vol 78 (1) ◽

pp. 34-38

Author(s):

Burcu BITERGE-SUT

Keyword(s):

Glioblastoma Multiforme ◽

Malignant Gliomas ◽

Genetic Alterations ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Lower Grade ◽

Nonsense Mutations ◽

Lower Grade Glioma ◽

Cancer Genome Atlas ◽

Genome Atlas

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.

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Identification of predictive biomarker for immunotherapy by associating with CD8+T cell Infiltration in lung adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21177 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21177-e21177

Author(s):

Puyuan Xing ◽

Teng Li ◽

Han Wang ◽

Lin Yang ◽

Guoqiang Wang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Predictive Biomarkers ◽

Tumor Infiltrating Lymphocytes ◽

Predictive Performance ◽

Predictive Biomarker ◽

Pooled Analysis ◽

The Cancer Genome Atlas ◽

T Cell Infiltration ◽

Or Groups ◽

Cancer Genome Atlas

e21177 Background: Tumor immune microenvironment (TIME) has been proved associated with response to immunotherapy(I/O). We hypothesized that screening potential mutation pattern which could significantly impact the tumor infiltrating lymphocytes(TILs) can help us to identify predictive biomarkers for I/O in Lung adenocarcinoma(LUAD). Methods: Multiple-dimensional data from The Cancer Genome Atlas LUAD cohort (n = 514) was used for building a mathematical model beween mutation signature and CD8+TIL score (based on MCP-counter). An independent public validation cohort (cohort 1: LUAD, n = 598) were used to assess the immunotherapeutic predictive performance of the potential mutation patterns. Results: Top 100 gene associated with CD8+TIL score were selected based on MC+ model which can provides the minimum non-convexity of the penalized loss given the level of bias. Seven TIME genes (SPTA1 coef 0.09; MET coef 0.02; HSD3B1 coef -0.00; STAT4 coef -0.01; EGFR coef -0.08; PIK3CB coef -0.08; KEAP1 coef -0.24) were generated by taking the intersection of the top 100 mutant genes and FoundationOne (F1) CDx NGS 315 genes panel and verified in cohort 1. Survival analysis showed that SPTA1mt was the only one that associated with both significantly longer PFS (median PFS 3.15 vs 2.89 months; HR 0.65; 95% CI 0.45 to 0.93; p = 0.02) and OS (median PFS 15.08 vs 7.36 months; HR 0.59; 95% CI 0.40 to 0.88; p = 0.01) for patients who received I/O compared with chemotherapy(CT) among seven TIME genes. In order to test our hypothesis fully, a pooled analysis of SPTA1mt (a core positive predictors of CD8+TILs) and KEAP1mt (a core negative predictors for CD8+TILs ) were conducted and yielded that co occurrence of SPTA1mt and KEAP1mt had a compound effects for TIME. The validation showed that co mutation with SPTA1mt was accompanied by an decrease HR for I/O vs. CT in both PFS (HR S+K vs. K only 0.59 vs 1.56) and OS (HR S+K vs. K only 0.39 vs 0.80) for KEAP1mt patients. Conclusions: Our data show that it is feasible to identify individuals or groups of individual with specific mutations to immunotherapy responses from TIME view. SPTA1mt was a core predictors for higher CD8+ TILs and can be identified as a predictive biomarker for benefit from I/O compared with CT. Prospective studies are warranted for further investigation.

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