A Combined Two-mRNA Signature Associated With PD-L1 and Tumor Mutational Burden for Prognosis of Lung Adenocarcinoma

Due to biological heterogeneity, lung adenocarcinoma (LUAD) patients with the same stage may exhibit variable responses to immunotherapy and a wide range of outcomes. It is urgent to seek a biomarker that can predict the prognosis and response to immunotherapy in these patients. In this study, we identified two genes (ANLN and ARNTL2) from multiple gene expression data sets, and developed a two-mRNA-based signature that can effectively distinguish high- and low-risk patients and predict patients’ response to immunotherapy. Furthermore, taking full advantage of the complementary value of clinical and molecular features, we combined the immune prognostic signature with clinical features to construct and validate a nomogram that can predict the probability of high tumor mutational burden (>10 mutations per megabyte). This may improve the estimation of immunotherapy response in LUAD patients, and provide a new perspective for clinical screening of immunotherapy beneficiaries.

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Identification of an Autophagy-Related lncRNA Prognostic Signature and Related Tumor Immunity Research in Lung Adenocarcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.767694 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hang Chen ◽

Zeyang Hu ◽

Menglu Sang ◽

Saiqi Ni ◽

Yao Lin ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Risk Score ◽

Checkpoint Inhibitors ◽

Enrichment Analysis ◽

Low Risk ◽

Immune Functions ◽

Mutational Burden ◽

Tumor Immune Microenvironment ◽

Tumor Mutational Burden ◽

Risk Patients

Autophagy is closely associated with the tumor immune microenvironment (TIME) and prognosis of patients with lung adenocarcinoma (LUAD). In the present study, we established a signature on the basis of long noncoding RNAs (lncRNAs) related to autophagy (ARlncRNAs) to investigate the TIME and survival of patients with LUAD. We selected ARlncRNAs associated with prognosis to construct a model and divided each sample into different groups on the basis of risk score. The ARlncRNA signature could be recognized as an independent prognostic factor for patients with LUAD, and patients in the low-risk group had a greater survival advantage. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analysis suggested that several immune functions and pathways were enriched in different groups. A high-risk score correlated significantly negatively with high abundance of immune cells and stromal cells around the tumor and high tumor mutational burden. Low-risk patients had a higher PD-1, CTLA-4, and HAVCR2 expression and had a better efficacy of immune checkpoint inhibitors, including PD-1/CTLA-4 inhibitor. A reliable signature on the basis of ARlncRNAs was constructed to explore the TIME and prognosis of patients with LUAD, which could provide valuable information for individualized LUAD treatment.

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MA19.05 Difference of Tumor Mutational Burden Is Associated with Distinct Immune Microenviroment in the T Cell-Inflamed Lung Adenocarcinoma

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2018.08.477 ◽

2018 ◽

Vol 13 (10) ◽

pp. S423

Author(s):

T. Karasaki ◽

K. Kitano ◽

K. Nagayama ◽

J. Nitadori ◽

M. Sato ◽

...

Keyword(s):

T Cell ◽

Lung Adenocarcinoma ◽

Mutational Burden ◽

Tumor Mutational Burden

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MiRNA expression patterns are associated with tumor mutational burden in lung adenocarcinoma

OncoImmunology ◽

10.1080/2162402x.2019.1629260 ◽

2019 ◽

Vol 8 (10) ◽

pp. e1629260

Author(s):

Yufeng Lv ◽

Zhong Huang ◽

Yan Lin ◽

Yuan Fang ◽

Zhichao Chen ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Mirna Expression ◽

Expression Patterns ◽

Mutational Burden ◽

Tumor Mutational Burden

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Defining tissue requirements for a reliable detection of tumor mutational burden (TMB) in clinical FFPE samples.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14265 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14265-e14265

Author(s):

Hans-Ulrich Schildhaus ◽

Thomas Herold ◽

Karl Worm ◽

Oliver Stoss

Keyword(s):

Predictive Biomarker ◽

Endoscopic Biopsy ◽

Cell Content ◽

Mutational Burden ◽

Wide Range ◽

Ffpe Samples ◽

Tumor Mutational Burden ◽

Minimum Requirements ◽

Tissue Size ◽

Definition Of

e14265 Background: In the context of immuno-oncology related cancer treatment, tumor mutational burden (TMB) is currently explored as a predictive biomarker for several human malignancies. Several sequencing assays are increasingly commercially available. Established methodologies require rather large amounts of DNA input (in the range of 100 ng) which, however, are frequently not available from small biopsies. We aim to investigate how tissue size and DNA input influence TMB scores. Methods: DNA from 20 specimens (12 biopsies of non-small cell lung cancer (NSCLC); 8 surgical resection specimens from NSCLC, colorectal cancer and endometrial carcinomas) was manually extracted by using the Qiagen GeneRead DNA FFPE kit. Cases were selected to provide a wide range of relative tumor cell content (from < 10% to > 50%) and to include microsatellite-stable and –instable (MSI) cases. Samples were analyzed in triplicates from predefined numbers of unstained sections of a standardized tissue size. DNA quantification was done fluorometrically and by qPCR. Up to 40 ng of DNA were analyzed with the QIASeq TMB Panel (incl. MSI primer boosters; Qiagen). Sequencing was done on an Illumina NextSeq platform, TMB scores and MSI status were determined by using the CLC workbench 5.0.1 (Qiagen). Results: Biopsy samples generated less numbers of DNA molecules (as detected by unique molecular identifiers, UMIs) and less overall reads compared to resection samples. UMI coverage was > 500x in all samples with > 15 ng DNA input. TMB scores were highly reproducible among all samples with > 15 ng DNA but differed significantly among samples with limited DNA input. Interestingly, TMB scores were inversely correlated with DNA input among those samples with < 15ng. Thus, valid TMB scores could also be obtained from only one slice of 1 cm2 tissue from tumor resections or 3 slices of an endoscopic biopsy (each of 5µm thickness). All pre-characterized MSI carcinomas could be detected correctly. Conclusions: We provide first evidence that TMB can be reliably determined also in small biopsies yielding limited DNA content. However, false high TMB scores can occur in samples with < 15ng DNA input. Our results contribute to the definition of minimum requirements (tissue size and DNA input) for valid TMB measurement on clinical FFPE samples.

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multiSLIDE: a web server for exploring connected elements of biological pathways in multi-omics data

10.1101/812271 ◽

2019 ◽

Author(s):

Soumita Ghosh ◽

Abhik Datta ◽

Hyungwon Choi

Keyword(s):

Keyword Search ◽

Data Sets ◽

Omics Data ◽

Web Based ◽

Molecular Features ◽

External Data ◽

Cluster Data ◽

Wide Range ◽

Time Basis ◽

Gene Ontologies

AbstractEmerging multi-omics experiments pose new challenges for exploration of quantitative data sets. We present multiSLIDE, a web-based interactive tool for simultaneous heatmap visualization of interconnected molecular features in multi-omics data sets. multiSLIDE operates by keyword search for visualizing biologically connected molecular features, such as genes in pathways and Gene Ontologies, offering convenient functionalities to rearrange, filter, and cluster data sets on a web browser in a real time basis. Various built-in querying mechanisms make it adaptable to diverse omics types, and visualizations are fully customizable. We demonstrate the versatility of the tool through three example studies, each of which showcases its applicability to a wide range of multi-omics data sets, ability to visualize the links between molecules at different granularities of measurement units, and the interface to incorporate inter-molecular relationship from external data sources into the visualization. Online and standalone versions of multiSLIDE are available at https://github.com/soumitag/multiSLIDE.

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Association of MSH2 Expression With Tumor Mutational Burden and the Immune Microenvironment in Lung Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2020.00168 ◽

2020 ◽

Vol 10 ◽

Cited By ~ 1

Author(s):

Mingming Jia ◽

Linli Yao ◽

Qin Yang ◽

Tian Chi

Keyword(s):

Lung Adenocarcinoma ◽

Immune Microenvironment ◽

Mutational Burden ◽

Tumor Mutational Burden

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A novel NCOR2-NTRK1 fusion detected in a patient of lung adenocarcinoma and response to larotrectinib: a case report

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01490-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lei Zhang ◽

Huanhuan Liu ◽

Ye Tian ◽

Huina Wang ◽

Xueying Yang

Keyword(s):

Targeted Therapy ◽

Lung Adenocarcinoma ◽

Ct Scan ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Molecular Profiling ◽

Case Presentation ◽

Mutational Burden ◽

Tumor Mutational Burden ◽

Breakpoint Location

Abstract Background The identification of NTRK fusions in tumours has become critically important due to the actionable events predictive of response to TRK inhibitor. It is not clear whether the NTRK breakpoint location is different for response to targeted therapy and NTRK fusions affects the efficacy of immunotherapy. Case presentation Here we reported a 60-year-old female diagnosed with advanced lung adenocarcinoma. NGS-based molecular profiling identified a novel NCOR2-NTRK1 fusion and high tumor mutational burden (TMB) (58.58 mutations/Mb) in this case. Additionally, program death-ligand 1 (PD-L1) expression was detected in 20–30% of the tumor cells by immunohistochemical (IHC) staining. The patient received treatment with anti-PD-1 immune checkpoint inhibitor of camrelizumab. After two cycles of treatment, the CT scan showed some tumor nodules were still enlarged, indicating disease progression. She was then changed to TRK inhibitor larotrectinib. One month later, the CT scan showed the volume of some lesions started to decrease, and no metastasis lesions were found. The patient then continued the administration of larotrectinib, and some lesion sizes were significantly reduced or even disappeared in the next few months. Currently, this patient is still alive. Conclusions Altogether, this report provided a new driver of lung adenocarcinoma expanded the mutational spectrum of NTRK1 fusion variants and suggested using larotrectinib as the targeted therapy is more effective than anti-PD-1 inhibitor in lung adenocarcinoma harboring with NTRK fusion, positive PD-L1 expression, and high TMB simultaneously.

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The landscape of ARID1A variants and correlation with tumor mutational burden in Chinese solid tumor patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14624 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14624-e14624

Author(s):

Jia Wei ◽

JieJie Zhang ◽

Qiang Wen ◽

Xiaoyi Zhu ◽

Dapeng Li ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Squamous Cell ◽

Lung Carcinoma ◽

Solid Tumor ◽

Immune Checkpoint ◽

Squamous Cell Lung Carcinoma ◽

Tumor Patients ◽

Cell Lung Carcinoma ◽

Mutational Burden ◽

Tumor Mutational Burden

e14624 Background: ARID1A (the AT-rich interaction domain 1A) is one of the most commonly mutated genes in cancer, mostly caused by frameshift variants. Here, we describe the mutational landscape of ARID1A in Chinese cancer patients and its correlation with tumor mutational burden (TMB). Methods: Formalin fixed paraffin embedded (FFPE) samples of 3,828 Chinese solid tumor patients were collected for next‐generation sequencing (NGS) based 450 genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangement were assessed. Microsatellite stable (MSS) status and TMB were also acquired by NGS algorithms. Results: A total of 340 (8.9%) patients were found to have ARID1A variants. The frequency of ARID1A mutations was 4% in lung adenocarcinoma (N = 74/1833), 8% in squamous cell lung carcinoma (N = 23/278), 12% in colorectal adenocarcinoma (N = 61/530), 11% in hepatocellular carcinoma (N = 52/484), 14% in pancreatic adenocarcinoma (N = 25/177), 15% in gallbladder adenocarcinoma (N = 14/94), 22% in intrahepatic cholangiocarcinoma (N = 47/213), 20% in gastric adenocarcinoma (N = 39/200) and 26% in endometrial adenocarcinoma (N = 5/19). ARID1A variants included truncation (78%), missense/indel (non-frameshift substitution/indel) (16%), splicing site (4%) and rearrangement (2%). Truncation was the most common, recurring in a few hot spots (R1276*, D1850Gfs*4, A339Lfs*24, P224Rfs*8 and Q372Afs*28/Sfs*19). In general, ARID1A mutations correlated with higher TMB (median 17.6 vs 7.4 muts/Mb, P < 0.001) in MSS tumors; especially in lung adenocarcinoma (17 vs 7.5 muts/Mb, P < 0.01), squamous cell lung carcinoma (16.8 vs 11.2 muts/Mb, P < 0.01). TP53 (60%), APC (34%) and KRAS (32%) were the most common co-occurred mutated gene in ARID1A (+) tumors. In more than 20% of ARID1A mutations, PI3K/mTOR pathway genes were altered, such as PIK3CA, PTEN, RNF43 and PIK3R1 genes. Conclusions: Since ARID1A mutations correlate with higher TMB, it could be a potential predictor of response to PD-1/PD-L1 immune checkpoint pathway inhibitors. As reported, ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Patients harboring ARID1A and PI3K/mTOR pathway mutations may provide useful information for drug discovery and biomarker exploration.

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