Tumor mutation burden analysis in a 5,660 cancer patient cohort reveals cancer type-specific mechanisms for high mutation burden.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2589-2589
Author(s):  
Xiaodong Jiao ◽  
Xiaochun Zhang ◽  
Baodong Qin ◽  
Dong Liu ◽  
Liang Liu ◽  
...  
Keyword(s):  
Effective Means ◽  
Lung Squamous Cell Carcinoma ◽  
Biological Pathways ◽  
Formalin Fixed Paraffin Embed ◽  
Cancer Type ◽  
Biological Mechanisms ◽  
Tumor Mutation Burden ◽  
Molecular Features ◽  
Mutation Burden ◽  
Cancer Types

2589 Background: Tumor mutation burden (TMB), calculated by whole-exome sequencing (WES) or large NGS panels, has an important association with immunotherapy responses. Elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. Meanwhile, the landscape of TMB across different cancer types and its association with other molecular features have not been well investigated in large cohorts in China. Methods: Cancer patients whose fresh tissue (n = 1556), formalin-fixed, paraffin-embed (FFPE) specimen (n = 1794), and pleural fluid (n = 84) were profiled using 295- or 520-gene NGS panel. The association of the TMB status with a series of molecular features and biological pathways was interrogated using bootstrapping. Results: TMB, measured by 295- or 520-cancer-related gene panels, were correlated with WES TMB based on in silico simulation in the TCGA cohort. We compared the TMB landscape across 11 cancer type groups and found the highest average TMB in lung squamous cell carcinoma, whereas the lowest TMB was established in sarcoma. High microsatellite instability, DNA damage response deficiency, and homologous recombination repair deficiency indicated significantly higher TMB. The independent predictive power for TMB of twenty-six biological pathways was tested in 10 cancer groups. FoxO signaling pathway most commonly correlated with low-TMB; significant association was identified in four cancer groups. In contrast, no pathway was significantly correlated with high-TMB in more than two cancer groups. Overall, we discovered that the underlying pathways which may be the main drivers of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 14- and 22-gene signature for TMB prediction for LUAD and LUSC, respectively, with only 10 genes shared by both signatures, indicating a histology-specific mechanism for driving high-TMB in lung cancer. Conclusions: The findings extended the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.

scholarly journals Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity

2019 ◽  
Author(s):  
Lin Li ◽  
Mengyuan Li ◽  
Xiaosheng Wang
Keyword(s):  
Antitumor Immunity ◽  
Colon Adenocarcinoma ◽  
Joint Effect ◽  
The Cancer Genome Atlas ◽  
Cancer Type ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Negative Role ◽  
Stomach Adenocarcinoma ◽  
Cancer Types

AbstractMany studies have shown thatTP53mutations play a negative role in antitumor immunity. However, a few studies reported thatTP53mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found thatTP53-mutated cancers had significantly higher levels of antitumor immune signatures thanTP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast,TP53-mutated cancers had significantly lower antitumor immune signature levels thanTP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover,TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) thanTP53-wildtype cancers. However, the TMB differences were more marked betweenTP53-mutated andTP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations betweenTP53mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused byTP53mutations on tumor immunity. Our data suggest that theTP53mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.

scholarly journals Cancer-specific associations of driver genes with immunotherapy outcome

2020 ◽  
Author(s):  
Tomi Jun ◽  
Tao Qing ◽  
Guanlan Dong ◽  
Maxim Signaevski ◽  
Julia F Hopkins ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Gene Mutations ◽  
Driver Gene ◽  
Oncogenic Signaling ◽  
Multiple Cancer ◽  
Driver Genes ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Types ◽  
Oncogenic Signaling Pathways

AbstractGenomic features such as microsatellite instability (MSI) and tumor mutation burden (TMB) are predictive of immune checkpoint inhibitor (ICI) response. However, they do not account for the functional effects of specific driver gene mutations, which may alter the immune microenvironment and influence immunotherapy outcomes. By analyzing a multi-cancer cohort of 1,525 ICI-treated patients, we identified 12 driver genes in 6 cancer types associated with treatment outcomes, including genes involved in oncogenic signaling pathways (NOTCH, WNT, FGFR) and chromatin remodeling. Mutations of PIK3CA, PBRM1, SMARCA4, and KMT2D were associated with worse outcomes across multiple cancer types. In comparison, genes showing cancer-specific associations—such as KEAP1, BRAF, and RNF43—harbored distinct variant types and variants, some of which were individually associated with outcomes. In colorectal cancer, a common RNF43 indel was a putative neoantigen associated with higher immune infiltration and favorable ICI outcomes. Finally, we showed that selected mutations were associated with PD-L1 status and could further stratify patient outcomes beyond MSI or TMB, highlighting their potential as biomarkers for immunotherapy.

scholarly journals Identifying Cancers Impacted by CDK8/19

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 821 ◽  
Author(s):  
Igor B. Roninson ◽  
Balázs Győrffy ◽  
Zachary T. Mack ◽  
Alexander A. Shtil ◽  
Michael S. Shtutman ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Clinical Samples ◽  
Tumor Mutation Burden ◽  
Binding Partner ◽  
Mutation Burden ◽  
Novel Drugs ◽  
Contrast Analysis ◽  
Cancer Types ◽  
Potential Impact ◽  
Tumor Types

CDK8 and CDK19 Mediator kinases are transcriptional co-regulators implicated in several types of cancer. Small-molecule CDK8/19 inhibitors have recently entered or are entering clinical trials, starting with breast cancer and acute myeloid leukemia (AML). To identify other cancers where these novel drugs may provide benefit, we queried genomic and transcriptomic databases for potential impact of CDK8, CDK19, or their binding partner CCNC. sgRNA analysis of a panel of tumor cell lines showed that most tumor types represented in the panel, except for some central nervous system tumors, were not dependent on these genes. In contrast, analysis of clinical samples for alterations in these genes revealed a high frequency of gene amplification in two highly aggressive subtypes of prostate cancer and in some cancers of the GI tract, breast, bladder, and sarcomas. Analysis of survival correlations identified a group of cancers where CDK8 expression correlated with shorter survival (notably breast, prostate, cervical cancers, and esophageal adenocarcinoma). In some cancers (AML, melanoma, ovarian, and others), such correlations were limited to samples with a below-median tumor mutation burden. These results suggest that Mediator kinases are especially important in cancers that are driven primarily by transcriptional rather than mutational changes and warrant an investigation of their role in additional cancer types.

PD-L1 expression landscape and its relationship with tumor mutation burden in Chinese cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15267-e15267
Author(s):  
Haihua Yang ◽  
Longgang Cui ◽  
Yuzi Zhang ◽  
Zhengyi Zhao ◽  
Yuezong Bai ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Expression Profiles ◽  
Chinese Patients ◽  
Cancer Type ◽  
Tissue Samples ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Chinese Cancer Patients

e15267 Background: Little is known about the pan-cancer PD-L1 expression landscape in Chinese patients although PD-L1 expression has been approved by FDA as a diagnosis for anti-PD-(L)1 therapy in several types of cancer. We did a cross-sectional analysis to assess the PD-L1 expression landscape in Chinese patients and its relationship with Tumor mutation burden (TMB). Methods: Tissue samples were collected from more than 8,000 consecutive cases in China between January, 2017, and August, 2019 and were analyzed by 3D Medicines, a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The method for NGS sequencing and tumor mutational burden (TMB) measurement were described previously. Clinical data and PD-L1 expression profiles were obtained from 8,063 patients whose tissue samples assed quality control. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay (Dako North America, Carpentaria, CA, U.S.) or Ventana PD-L1 SP263 assay (Ventana Medical Systems, Tucson, AZ, U.S.). PD-L1 expression was determined using Tumor Proportion Score (TPS), the percentage of viable tumor cells stained. Results: PD-L1 expression was examined for 8,063 tissue samples collected from more than 18 different types of solid tumors. There were 4,866 (60%) male and 3,197 (40%) female patients. Their median age was 59 (IQR range, 50-66) years. Given the significance of different cut-points of PD-L1 expression in predicting clinical outcomes, expression levels of PD-L1 were arranged into the following intervals: < 1%, 1%-5%, 5%-50% and ≥50% for each cancer type. Small cell lung cancer (SCLC) had the lowest and Squamous Carcinoma of Head and Neck (HNSC) had the highest levels of PD-L1 expression. Spearman correlation analysis indicated no correlation between PD-L1 and tumor mutational burden (TMB) for Chinese cancer patients (R = 0.1, P < 0.01), which is in line with the previous reports that PD-L1 and TMB were two independent predictors in immunotherapy. Conclusions: The landscape of PD-L1 expression among Chinese cancer population in this study will further assist the utilization of PD-L1 as a predictive biomarker in clinical practice.

scholarly journals Tumor mutation burden in Chinese cancer patients and the underlying driving pathways of high tumor mutation burden across different cancer types

2020 ◽  
Vol 8 (14) ◽  
pp. 860-860
Author(s):  
Xiao-Dong Jiao ◽  
Xiao-Chun Zhang ◽  
Bao-Dong Qin ◽  
Dong Liu ◽  
Liang Liu ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Types ◽  
Chinese Cancer Patients

scholarly journals Identifying cancer type specific oncogenes and tumor suppressors using limited size data

2016 ◽  
Vol 14 (06) ◽  
pp. 1650031 ◽  
Author(s):  
Ana B. Pavel ◽  
Cristian I. Vasile
Keyword(s):  
Tumor Suppressors ◽  
Molecular Mechanisms ◽  
Lung Squamous Cell Carcinoma ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Cancer Type ◽  
Multiple Cancer ◽  
Driver Genes ◽  
Cancer Subtypes ◽  
Cancer Types

Cancer is a complex and heterogeneous genetic disease. Different mutations and dysregulated molecular mechanisms alter the pathways that lead to cell proliferation. In this paper, we explore a method which classifies genes into oncogenes (ONGs) and tumor suppressors. We optimize this method to identify specific (ONGs) and tumor suppressors for breast cancer, lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and colon adenocarcinoma (COAD), using data from the cancer genome atlas (TCGA). A set of genes were previously classified as ONGs and tumor suppressors across multiple cancer types (Science 2013). Each gene was assigned an ONG score and a tumor suppressor score based on the frequency of its driver mutations across all variants from the catalogue of somatic mutations in cancer (COSMIC). We evaluate and optimize this approach within different cancer types from TCGA. We are able to determine known driver genes for each of the four cancer types. After establishing the baseline parameters for each cancer type, we identify new driver genes for each cancer type, and the molecular pathways that are highly affected by them. Our methodology is general and can be applied to different cancer subtypes to identify specific driver genes and improve personalized therapy.

scholarly journals KIF18B is a Prognostic Biomarker and Correlates with Immune Infiltrates in Pan-Cancer

2021 ◽  
Vol 8 ◽  
Author(s):  
Meng-jun Qiu ◽  
Qiu-shuang Wang ◽  
Qiu-ting Li ◽  
Li-sheng Zhu ◽  
Ya-nan Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Cell ◽  
Prognostic Biomarker ◽  
Tumor Mutation Burden ◽  
R Language ◽  
Normal Tissues ◽  
Expression Difference ◽  
Mutation Burden ◽  
Cancer Types ◽  
Pan Cancer

Background: Cancer is one of the deadliest diseases at present. Although effective screening and treatment can save lives to a certain extent, our knowledge of the disease is far from sufficient. KIF18B is a member of the kinesin-8 superfamily and plays a conserved regulatory role in the cell cycle. KIF18B reportedly functions as an oncogene in some human cancers, but the correlations between KIF18B and prognosis and immune-infiltrates in different cancers remain unclear.Methods: Data were collected from the TCGA, GTEx, CCLE, TIMER, and GSEA databases. The expression difference, survival, pathological stage, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repairs (MMRs), tumor microenvironment (TME), immune cell infiltration, and gene co-expression of KIF18B were analyzed using the R language software.Results: KIF18B was widely upregulated in cancers, compared with normal tissues, and high KIF18B expression was associated with unfavorable prognoses. TMB, MSI, MMRs, and DNA methylation correlated with KIF18B dysregulation in cancers. KIF18B correlated closely with tumor immunity and interacted with different immune cells and genes in different cancer types.Conclusion: KIF18B could be used as a prognostic biomarker for determining prognosis and immune infiltration in pan-cancer.

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