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

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.

Download Full-text

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.

Download Full-text

Co-occurring alteration of NOTCH and DDR pathways serve as novel predictor to efficacious immunotherapy in NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21106 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21106-e21106

Author(s):

Zhimin Zhang ◽

Yanyan Gu ◽

Xiaona Su ◽

Jing Bai ◽

Wei Guan ◽

...

Keyword(s):

Progressive Disease ◽

Checkpoint Inhibitors ◽

Notch Pathway ◽

Progression Free Survival ◽

The Cancer Genome Atlas ◽

Expression Data ◽

Free Survival ◽

Future Clinical Practice ◽

Cancer Genome Atlas ◽

Nsclc Patients

e21106 Background: Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the majority produce an ultra-rapid progressive disease. Methods: Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. 106 NSCLC patients treated with immunotherapy were combined from Rizvi et. al and Hellman et. al studies (whole exon sequencing) as the discovery dataset. Two independent validation datasets were comprised of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. Results: In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [ 22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [ Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96 ; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1 ]. By analyzing TCGA cohort, we found patients with coexisting NOTCH and co-DDR pathway had a higher TMB, more infiltration of CD4+T cells. Conclusions: Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.

Download Full-text

Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC

Frontiers in Oncology ◽

10.3389/fonc.2021.659321 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhimin Zhang ◽

Yanyan Gu ◽

Xiaona Su ◽

Jing Bai ◽

Wei Guan ◽

...

Keyword(s):

Progressive Disease ◽

Checkpoint Inhibitors ◽

Notch Pathway ◽

Progression Free Survival ◽

The Cancer Genome Atlas ◽

Expression Data ◽

Free Survival ◽

Future Clinical Practice ◽

Cancer Genome Atlas ◽

Nsclc Patients

Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2–0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31–0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18–1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.

Download Full-text

Immune checkpoint inhibitors (ICI) response in metastatic non-small cell lung cancer (NSCLC) patients with WNT pathway mutations (APC/CTNNB1).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15137 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15137-e15137

Author(s):

Patricia Iranzo ◽

Ana Callejo ◽

Anna Pedrola ◽

Nuria Pardo Aranda ◽

Alejandro Navarro ◽

...

Keyword(s):

Lung Cancer ◽

Wnt Pathway ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Whole Exome ◽

Pathway Activation ◽

Metastatic Setting ◽

Targeted Ngs ◽

Unknown Significance ◽

Nsclc Patients

e15137 Background: APC and CTNNB1 mutations (mut) lead to an aberrant activation of the WNT pathway which has been linked to lack of benefit of immunotherapy in patients (pts) with lung cancer. Our aim is to describe the pts’ characteristics of a NSCLC cohort with APC or CTNNB1 mut and their association with outcomes (Overall survival [OS] and Progression-Free-Survival [PFS]) when treated with ICI. Methods: We selected NSCLC pts with mut in APC or CTNNB1 by targeted NGS (tissue), whole exome sequencing (tissue) or Guardant 360(plasma) between January 2014 and October 2019. Functionality of mut and β-catenin protein expression by immunohistochemistry (IHC) were correlated with outcome. Results: We identified a total of 37 patients with 44 mutually-exclusive mutations in APC (31) or CTNNB1 (6), 25 adenocarcinomas (68%). Of APC mut cohort, 16 had pathogenic mut (52%) and 15 of unknown significance (48%). All 6 CTN NB1 mut were known pathogenic. Median OS (mOS) in metastatic setting was 21.6 months (m) (CI95% 14.9-NR), without differences between APC and CTNNB1 groups (HR 1.5, p = 0.4) or when stratified by mut functionality (HR 1.1, p = 0.8). Globally, 21 pts received treatment with ICI (57%, 19 APC, 2 CTNNB1), median PFS (mPFS) was 5.43m (1.8-21.7), with trend for shorter mPFS in CTNNB1 mut (mPFS 1.7m) vs. APC mut (mPFS 6.6m, HR 1.5, p = 0.1). Among patients treated with ICI, 8 (38%) had coexisting driver targetable alterations ( EGFR, ERBB2 or MET) and 13 (62%) other functional mut were found ( TP53, KRAS, STK11, BRCA2, ATM). mPFS was 3.9m (1.8-NR) in the subgroup with driver mut vs. 6.6m (1.4-NR) for remaining pts (HR 1.36, p = 0.5). In 15 pts β-catenin IHC was performed, being positive in 7 cases (47%), 4 of them received ICI with a mPFS 12.1m. Conclusions: In our experience, benefit with ICI is not influenced by the presence of APC mut, and small numbers of CTNNB1 cohort limit conclusive statements. Additional studies are required to assess WNT pathway activation on top of genomics and correlate with the ICI efficacy.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13661 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13661-e13661

Author(s):

Xiang Wang ◽

Ding Zhang ◽

Guoqiang Wang ◽

Anqi Duan ◽

Xiang Ruan ◽

...

Keyword(s):

Copy Number ◽

Checkpoint Inhibitors ◽

Predictive Biomarker ◽

Copy Number Gain ◽

The Cancer Genome Atlas ◽

Missense Mutations ◽

Nonsense Mutations ◽

Positive Rate ◽

Cancer Genome Atlas ◽

Copy Number Amplification

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.

Download Full-text

Optimal next-generation sequencing (NGS) panel for estimating tumor mutation burden (TMB) and its clinical implication for non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9097 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9097-9097

Author(s):

Takaya Ikeda ◽

Hajime Oi ◽

Kiyotaka Yoh ◽

Shingo Matsumoto ◽

Terufumi Kato ◽

...

Keyword(s):

Lung Cancer ◽

Squamous Cell ◽

Clinical Utility ◽

Checkpoint Inhibitors ◽

Genomic Analysis ◽

Progression Free Survival ◽

Median Number ◽

Lung Cancer Patients ◽

Mutation Burden ◽

Nsclc Patients

9097 Background: TMB estimation using targeted NGS panels is widely performed in clinical practice. The objective of this study was to determine the optimal NGS panel for estimating TMB and to evaluate its clinical implications for NSCLC. Methods: Two NGS panels, Oncomine Tumor Mutation Load Assay (OMLA) and FoundationOne (F1), were compared to select the most accurate TMB prediction panel. From February 2017 to May 2018, 350 lung cancer patients were analyzed by whole-exome sequencing (WES), and the concordance rate of OMLA and F1 to WES was examined. In addition, its clinical utility as a biomarker for immune checkpoint inhibitors (ICIs) was evaluated in our international genome screening network (LC-SCRUM-Asia). From June 2019 to December 2020, 3141 patients with NSCLC from 185 institutions were enrolled, and genomic analysis was successful. The clinico-genomic database of LC-SCRUM-Asia was used for this analysis. Results: The linear correlation with WES was 0.80 for OMLA and 0.78 for F1. This indicated that OMLA was more strongly correlated with WES. The cutoff value of F1 was 10 mut/Mb, which corresponded to 9 mut/Mb (OMLA) and 194 mutations (WES). The sensitivity of the OMLA for WES was 79%, and the specificity was 85%. Meanwhile, the sensitivity of the F1 was 74%, and the specificity was 80%. OMLA more accurately predicted TMB, and its clinical utility was evaluated. 3141 NSCLC patients, consisting of 2282 adenocarcinomas, 593 squamous cell carcinomas, and 266 others, were analyzed for TMB, estimated using OMLA. The median number of mutations was 4.2 mut/Mb (range, 0-718.4/Mb). High TMB (≥9 mut/Mb) was observed in 17.2% (393/2282) of adenocarcinoma cases and 25.8% (153/593) in squamous cell carcinoma cases. 778 patients were treated with ICI or ICI plus chemotherapy as the first-line treatment. Patients’ characteristics were as follows: male/female; 595/183, median age (range); 67 (25-90), stage II/III/VI/recurrence; 11/90/649/28, TMB high/low; 177/601, ICI/ICI plus chemotherapy; 114/664. The progression-free survival (PFS) was significantly longer in patients with high TMB than in those with low TMB (median PFS, 7.5 vs. 5.9 months, p = 0.0314). The overall survival (OS) was significantly longer in patients with high TMB than in those with low TMB (median OS, 27.4 vs. 20.4 months, p = 0.006). Conclusions: The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1. TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs. Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.

Download Full-text

Comprehensive Analysis of m6A Regulators Characterized by the Immune Cell Infiltration in Head and Neck Squamous Cell Carcinoma to Aid Immunotherapy and Chemotherapy

Frontiers in Oncology ◽

10.3389/fonc.2021.764798 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhiqiang Yang ◽

Xiaoping Ming ◽

Shuo Huang ◽

Minlan Yang ◽

Xuhong Zhou ◽

...

Keyword(s):

Overall Survival ◽

Immune Cell ◽

Comprehensive Evaluation ◽

Principal Component ◽

Response To Therapy ◽

The Cancer Genome Atlas ◽

Mutation Burden ◽

Number Variation ◽

Clinical Benefits ◽

Cancer Genome Atlas

BackgroundN6-Methyladenosine (m6A), which is a prevalent regulator of mRNA expression, has gathered increasing study interests. Though the role of m6A as being important in many biological processes (such as growth and proliferation of cancers) has been well documented, its potential role in tumor immune microenvironment (TIME) has rarely been analyzed.MethodsWe downloaded RNA expression, single nucleotide polymorphism (SNP), and copy number variation (CNV) data from The Cancer Genome Atlas (TCGA). We then curated 21 m6A regulators and clustered patients into three m6A subtypes and m6A-related gene subtypes and compared them based on overall survival (OS). The combination of CIBERSORT as well as ssGSEA quantified the infiltration levels of immune cells and immune-related functions. The m6A scores were determined by using principal component analysis (PCA) algorithm. Furthermore, we evaluate the correlation of m6A regulators with immune and response to therapy.ResultsThree m6A clusters were identified based on the TCGA-HNSCC cohort, and there were significant associations among them in overall outcomes and caner-related pathways. We found that three m6A clusters were consistent with three phenotypes: immune-inflamed, immune-dessert, and immune-excluded. HNSCC patients were divided into high– and low–m6A score groups based on the cutoff of m6A score. Patients with lower m6A score had better overall survival outcome. Further analysis indicated that patients with higher m6A score presented higher tumor mutation burden (TMB). In addition, patients in low–m6A score subgroup had high chemotherapeutics sensitivity. GEO cohort confirmed patients with low m6A score demonstrated significant overall survival advantages and clinical benefits. Low m6A score carry an increased neoantigen load, eliciting a response to immunotherapy, and its value in predicting survival outcomes of immunotherapy was also confirmed in three anti-PD-1 cohorts.ConclusionsOur study demonstrated that m6A regulators are closely related to TIME and the m6A score was an effective prognostic biomarker and predictive indicator for immunotherapy and chemotherapeutics. Comprehensive evaluation of m6A regulators in tumors will extend our understanding of TIME and effectively guide increasing study investigations on immunotherapy and chemotherapy strategies for HNSCC.

Download Full-text

Comparison of commonly used solid tumor targeted gene sequencing panels for estimating tumor mutation burden shows analytical and prognostic concordance within the cancer genome atlas cohort

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000613 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000613

Author(s):

Nicholas Bevins ◽

Shulei Sun ◽

Zied Gaieb ◽

John A Thorson ◽

Sarah S Murray

Keyword(s):

Solid Tumor ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Tumor Mutation Burden ◽

Whole Exome ◽

Mutation Burden ◽

Cancer Genome Atlas ◽

Gene Panels ◽

The Impact ◽

Genome Atlas

BackgroundTumor mutation burden (TMB) is a biomarker frequently reported by clinical laboratories, which is derived by quantifying of the number of single nucleotide or indel variants (mutations) identified by next-generation sequencing of tumors. TMB values can inform prognosis or predict the response of a patient’s tumor to immune checkpoint inhibitor therapy. Methods for the calculation of TMB are not standardized between laboratories, with significant variables being the gene content of the panels sequenced and the inclusion or exclusion of synonymous variants in the calculations. The impact of these methodological differences has not been investigated and the concordance of reported TMB values between laboratories is unknown.MethodsSequence variant lists from more than 9000 tumors of various types were downloaded from The Cancer Genome Atlas. Variant lists were filtered to include only appropriate variant types (ie, non-synonymous only or synonymous and non-synonymous variants) within the genes found in five commonly used targeted solid tumor gene panels as well as an in-house gene panel. Calculated TMB was paired with corresponding overall survival (OS) data of each patient.ResultsRegression analysis indicates high concordance of TMB as derived from the examined panels. TMB derived from panels was consistently and significantly lower than that derived from a whole exome. TMB, as derived from whole exome or the examined panels, showed a significant correlation with OS in the examined data.ConclusionsTMB derived from the examined gene panels was analytically equivalent between panels, but not between panels and whole-exome sequencing. Correlation between TMB and OS is significant if TMB method-specific cut-offs are used. These results suggest that TMB values, as derived from the gene panels examined, are analytically and prognostically equivalent.

Download Full-text

Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors

JCO Precision Oncology ◽

10.1200/po.17.00146 ◽

2017 ◽

pp. 1-13 ◽

Cited By ~ 12

Author(s):

Anshuman Panda ◽

Anil Betigeri ◽

Kalyanasundaram Subramanian ◽

Jeffrey S. Ross ◽

Dean C. Pavlick ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

The Cancer Genome Atlas ◽

Checkpoint Activation ◽

Mutational Burden ◽

Whole Exome ◽

Cancer Genome Atlas ◽

Cancer Types ◽

Genome Atlas

Purpose An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing or by using commercially available sequencing panels. Methods Whole-exome sequencing and RNA sequencing data of 33 solid cancer types from The Cancer Genome Atlas were analyzed to determine whether a robust immune checkpoint–activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker of response to immune checkpoint blockade therapy. Results We found that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in eight of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer, and bladder-urothelial cancer. Tumors with a mutational burden higher than the threshold (iCAM positive) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma, and colon cancer, patients with iCAM-positive tumors had significantly better response to immune checkpoint therapy compared with those with iCAM-negative tumors. Receiver operating characteristic analysis using The Cancer Genome Atlas predictions as the gold standard showed that iCAM-positive tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne (Foundation Medicine, Cambridge, MA) or StrandAdvantage (Strand Life Sciences, Bangalore, India). Using the FoundationOne-derived threshold, an analysis of 113 melanoma tumors showed that patients with iCAM-positive disease have significantly better response to immune checkpoint therapy. iCAM-positive and iCAM-negative tumors have distinct mutation patterns and different immune microenvironments. Conclusion In eight solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.

Download Full-text

The pattern of alternative splicing in lung adenocarcinoma shows novel events correlated with tumorigenesis and immune microenvironment

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01776-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Gongjun Wang ◽

Weiwei Qi ◽

Liwei Shen ◽

Shasha Wang ◽

Ruoxi Xiao ◽

...

Keyword(s):

Alternative Splicing ◽

Lung Adenocarcinoma ◽

Immune Cells ◽

Risk Group ◽

Progression Free Survival ◽

High Risk Group ◽

The Cancer Genome Atlas ◽

Normal Tissues ◽

Cancer Genome Atlas ◽

Score Model

AbstractLung adenocarcinoma (LUAD) is the leading cause of cancer deaths worldwide due to the lack of early diagnostic markers and specific drugs. Previous studies have shown the association of LUAD growth with aberrant alternative splicing (AS). Herein, clinical data of 535 tumor tissues and 59 normal tissues were extracted from The Cancer Genome Atlas (TCGA) database. Each sample was analyzed using the ESTIMATE algorithm; a comparison between higher and lower score groups (stromal or immune) was made to determine the overall- and progression-free survival-related differentially expressed AS (DEAS) events. We then performed unsupervised clustering of these DEASs, followed by determining their relationship with survival rate, immune cells, and the tumor microenvironment (TME). Next, two prognostic signatures were developed using bioinformatics tools to explore the prognosis of cases with LUAD. Five OS- and six PFS-associated DEAS events were implemented to establish a prognostic risk score model. When compared to the high-risk group (HRG), the PFS and OS of the low-risk group (LRG) were found to be considerable. Additionally, a better prognosis was found considerably associated with the ESTIMATE score of the patients as well as immune cells infiltration. Our analysis of AS events in LUAD not only helps to clarify the tumorigenesis mechanism of AS but also provides ideas for revealing potential prognostic biomarkers and therapeutic targets.

Download Full-text