495 Basal cell carcinoma demonstrates a T-cell exclusion immune phenotype in contrast to other anti-PD-1 therapy responsive cutaneous malignancies

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A530-A530
Author(s):  
Geoffrey Gibney ◽  
Joanne Xiu ◽  
Gino In ◽  
Steven O’Day ◽  
Jose Lutzky ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Cell Carcinoma ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Population Abundance ◽  
Gene Set Enrichment ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
T Cell Exclusion

BackgroundBasal cell carcinoma (BCC) is considered an immunogenic tumor based on the high tumor mutational burden (TMB), increased incidence in immunocompromised patients, and responsiveness to imiquimod, a toll-like receptor agonist therapy. However, anti-PD-1 immunotherapy response rates in patients with advanced BCC appear less than that seen with other advanced cutaneous malignancies. Molecular profiles of BCC tumors were analyzed to determine immune phenotypes and resistance mechanisms in comparison to other anti-PD-1 therapy responsive cutaneous malignancies.MethodsNext generation sequencing on DNA (NGS; NextSeq and Novaseq), PD-L1 immunohistochemistry (SP-142 and 28–8 antibody clones, cutoff >5% tumor staining) and mRNA gene expression level (Whole Transcriptome Sequencing, NovaSeq) data from BCC (N=69), melanoma (N=914), and cutaneous squamous cell carcinoma (SCC) tumors (N=165) at Caris Life Sciences (Phoenix, AZ) were analyzed. Tumor mutational burden (TMB) was calculated by counting all non-synonymous missense mutations that had not been previously described as germline alterations. Microenvironment cell population counter1 was used to estimate cell population abundance in the TME. Gene set enrichment analysis (GSEA) was performed on transcriptomes.2 Statistical significance was set at P value or false discovery rate (FDR) < 0.05.ResultsOf the 69 BCC tumors with NGS data, the most frequent mutations were in PTCH1 (82%), P53 (73%) and ARID1A (42%); additional relevant mutations included SMO (18%), JAK1 (9%), PI3KCA (6%), APC (4%), and CTNNB1 (3%). TMB was significantly greater in BCC compared to melanoma (median 30.5 vs 12 mut/Mb, P<0.0001) and similar to SCC (median 29.5 mut/Mb, P=0.9389). PD-L1 positivity was 1/23 (4%) in BCC, 215/831 (26%) in melanoma, and 81/147 (56%) in SCC. Interferon gamma and T-effector immune gene analyses showed significantly lower expression in BCC compared to melanoma and SCC (e.g., IFNg TPM=0.26 (BCC) vs 0.65 and 0.58 (melanoma, SCC, both P<0.01). BCC demonstrated the lowest CD-8 T-cell fractions and the highest neutrophil and cancer associated fibroblast (CAF) fractions compared to melanoma and SCC. Angiogenesis and TGF-beta gene sets were enriched in BCC compared to melanoma (NES=1.5, FDR=0.046 and NES=1.35, FDR=0.055, respectively), but not compared to SCC (NES=0.90, FDR=0.57 and NES=0.94, FDR=0.60, respectively).ConclusionsWhile BCC tumors demonstrated a high TMB, a markedly lower level of adaptive anti-tumor immunity in comparison to other cutaneous malignancies was observed. T-cell exclusion mechanisms mediated through CAFs and desmoplasia, with upregulation of TGF-beta and angiogenic signaling, may play a role. Further investigation into abrogation of these mechanisms is warranted to develop improved anti-PD-1 based therapies for BCC.ReferencesBecht E, Giraldo NA, Lacroix L, Buttard B, Elarouci N, Petitprez F, Selves J, Laurent-Puig P, Sautès-Fridman C, Fridman WH, de Reyniès A. Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression. Genome Biol 2016; 17(1):218.Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005;102(43):15545–50.

scholarly journals Revealing Biological Pathways Implicated in Lung Cancer from TCGA Gene Expression Data Using Gene Set Enrichment Analysis

2014 ◽  
Vol 13s1 ◽  
pp. CIN.S13882 ◽  
Author(s):  
Binghuang Cai ◽  
Xia Jiang
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Gene Expression Data ◽  
Lung Squamous Cell Carcinoma ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Expression Data ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Pathway Gene

Analyzing biological system abnormalities in cancer patients based on measures of biological entities, such as gene expression levels, is an important and challenging problem. This paper applies existing methods, Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis, to pathway abnormality analysis in lung cancer using microarray gene expression data. Gene expression data from studies of Lung Squamous Cell Carcinoma (LUSC) in The Cancer Genome Atlas project, and pathway gene set data from the Kyoto Encyclopedia of Genes and Genomes were used to analyze the relationship between pathways and phenotypes. Results, in the form of pathway rankings, indicate that some pathways may behave abnormally in LUSC. For example, both the cell cycle and viral carcinogenesis pathways ranked very high in LUSC. Furthermore, some pathways that are known to be associated with cancer, such as the p53 and the PI3K-Akt signal transduction pathways, were found to rank high in LUSC. Other pathways, such as bladder cancer and thyroid cancer pathways, were also ranked high in LUSC.

Differential gene expression in prostate tissue according to vasectomy.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 298-298
Author(s):  
Kathryn M Wilson ◽  
Travis Gerke ◽  
Ericka Ebot ◽  
Jennifer A Sinnott ◽  
Jennifer R. Rider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Diagnosis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Prostate Tissue ◽  
Gene Set Enrichment ◽  
Normal Prostate ◽  
Gene Sets ◽  
Normal Prostate Tissue

298 Background: We previously found that vasectomy was associated with an increased risk of prostate cancer, and particularly, risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS). However, the possible biological basis for this finding is unclear. In this study, we explored possible biological mechanisms by assessing differences in gene expression in the prostate tissue of men with and without a history of vasectomy prostate cancer diagnosis. Methods: Within the HPFS, vasectomy data and gene expression data (20,254 genes) was available from archival tumor tissue from 263 cases, 124 of whom also had data for adjacent normal tissue. To relate expression of individual genes to vasectomy we used linear regression adjusting for age and year at diagnosis. We ran gene set enrichment analysis to identify pathways of genes associated with vasectomy. Results: Among 263 cases, 67 (25%) reported a vasectomy prior to cancer diagnosis. Mean age at diagnosis was 66 years among men without and 65 years among men with vasectomy. Median time between vasectomy and prostate cancer diagnosis was 25 years. Gene expression in tumor tissue was not associated with vasectomy status. In adjacent normal tissue, three individual genes were associated with vasectomy with Bonferroni-corrected p-values of < 0.10: RAPGEF6, OR4C3, and SLC35F4. Gene set enrichment analysis found five pathways upregulated and seven pathways downregulated in men with vasectomy compared to those without in normal prostate tissue with a FDR < 0.05. Upregulated pathways included several immune-related gene sets and G-protein-coupled receptor gene sets. Conclusions: We identified significant differences in gene expression profiles in normal prostate tissue according to vasectomy status among men treated for prostate cancer. The fact that such differences existed several decades after vasectomy provides support for the idea that vasectomy may play a role in the etiology of prostate cancer.

scholarly journals A Comparative Study of Mouse Hepatic and Intestinal Gene Expression Profiles under PPARαKnockout by Gene Set Enrichment Analysis

PPAR Research ◽  
2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Kan He ◽  
Qishan Wang ◽  
Yumei Yang ◽  
Minghui Wang ◽  
Yuchun Pan
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Enrichment Analysis ◽  
Small Cell ◽  
Gene Set Enrichment Analysis ◽  
Small Cell Lung ◽  
Gene Set Enrichment ◽  
Tissue Specific

Gene expression profiling of PPARαhas been used in several studies, but fewer studies went further to identify the tissue-specific pathways or genes involved in PPARαactivation in genome-wide. Here, we employed and applied gene set enrichment analysis to two microarray datasets both PPARαrelated respectively in mouse liver and intestine. We suggested that the regulatory mechanism of PPARαactivation by WY14643 in mouse small intestine is more complicated than in liver due to more involved pathways. Several pathways were cancer-related such as pancreatic cancer and small cell lung cancer, which indicated that PPARαmay have an important role in prevention of cancer development. 12 PPARαdependent pathways and 4 PPARαindependent pathways were identified highly common in both liver and intestine of mice. Most of them were metabolism related, such as fatty acid metabolism, tryptophan metabolism, pyruvate metabolism with regard to PPARαregulation but gluconeogenesis and propanoate metabolism independent of PPARαregulation. Keratan sulfate biosynthesis, the pathway of regulation of actin cytoskeleton, the pathways associated with prostate cancer and small cell lung cancer were not identified as hepatic PPARαindependent but as WY14643 dependent ones in intestinal study. We also provided some novel hepatic tissue-specific marker genes.

Gene expression combined with gene set enrichment analysis to identify markers of vinorelbine efficacy in breast cancer patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e21099-e21099
Author(s):  
Robert Audet ◽  
Changyu Shen ◽  
Scooter Willis ◽  
Renata Duchnowska ◽  
Krzysztof Adamowicz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Chromosomal Location ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Molecular Function ◽  
Time To Progression ◽  
Gene Set Enrichment ◽  
Histone Binding

e21099 Background: Vinorelbine (V) induces mitotic arrest and apoptosis but there are limited data on its effect on gene expression in breast cancer clinical setting. Methods: 43 adult female patients with pathologically confirmed breast cancer and locally advanced or metastatic disease were treated with V 25 mg/m2 days 1, 8, 15 of a 28-day cycle. Gene expression was assessed in archival FFPE tissue using the microarray-based DASL assay (cDNA-mediated Annealing, Selection extension and Ligation) and correlated with time-to-progression (TTP). Using a Gene Set Enrichment Analysis (GSEA), groups of genes that share a common molecular function, chromosomal location, or regulation were identified in patients classified as having either a short (S) (n=25) or a long (L) (n=18) time to progression (TTP) divided by the median (72 days). The GSEA software ( http://www.broadinstitute.org/gsea/index.jsp ) was used for the analysis. Results: GSEA focusing on genes grouped according to similar a) molecular function: 16 out of a set of 43 genes involved in histone binding were enriched in group S (p = 0.002), consistent with higher expression in group S of HIST3H2BB and HIST1H3I as well as a nuclear transcription factor promoting their expression. b) transcription factors: 14 out of 47 genes were enriched in group S (p = 0.004) and corresponds to genes with promoter regions that match c-fos serum response element-binding transcription factor that modulates, for example, ABCC1 and ABCB1 (P-gp/MDR1) solute carriers. c) chromosomal location: in group S, genes were enriched on chromosome 11q21 (20 out of 45 genes p = 0.004) and on chromosome 12p12 (14 out of 22 genes p = 0.002). Conclusions: a) the up-regulation of histone binding genes is consonant with recent discovery of high affinity V binding to histones b) the role of P-gp/MDR1 in V transport is well known c) our observations on chromosome 11q21 and12p12 are novel. DASL expression combined with GSEA highlights gene sets that correlate with clinical outcome and may lead to predictive markers of V efficacy. Further confirmatory analysis is needed due to the limitation of small sample size and multiple comparisons.

Gene Set Enrichment Analysis of Ki-67high CLL Clones Suggests Complex Interactions of B-Cell Receptor Signaling and Normal Cell Interactions in the Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2833-2833
Author(s):  
Xiao J. Yan ◽  
Daniel Kalenscher ◽  
Erin Boyle ◽  
Sophia Yancopoulos ◽  
Rajendra N Damle ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Ki 67 ◽  
Mutation Status ◽  
Gene Set ◽  
Gene Sets ◽  
Bcr Signaling

Abstract Abstract 2833 Introduction: In chronic lymphocytic leukemia (CLL), clonally expanded CD5+ B lymphocytes eventually overwhelm healthy immune cells, hindering normal immune function. To determine mechanisms fueling this expansion, gene expression data were gathered by microarray analysis of cells from CLL patients. Samples were grouped based on Ki-67 expression, an indicator of proliferation. To determine mechanisms correlating with B-cell proliferation and impacting on CLL B-cell biology, microarray profiles were compared using Gene Set Enrichment Analysis (GSEA) [Subramanian A, et al. PNAS 2005]. Methods: Samples were analyzed for intracellular expression of Ki-67 by flow cytometry and divided into 2 groups based on Ki-67 expression (cutoff at 5%). RNA was then purified from CD5+CD19+ CLL cells and gene expression microarray assays were performed using Illumina HumanHT12 beadchips. GSEA was carried out using a library of signatures by Dr. Louis Staudt [Shaffer AL, et al. Immunol Rev 2006] containing 305 gene sets encompassing 13, 564 genes biased towards hematopoietic signatures. Results: Of 61 cases, 14 were Ki-67high and 47 were Ki-67low. When time-to-first-treatment (TTFT) was compared between the groups, Ki67high patients had significantly shorter TTFT (2.76 yrs) compared to Ki-67low patients (23.46 yrs; P<0.0001). By GSEA, we determined 255/285 gene sets were upregulated in the Ki-67high group with 50 gene sets significantly enriched at a false discovery rate (FDR) <25%. For the Ki-67low group, 30/285 gene sets were upregulated with only one significant at FDR <25%. IGHV unmutated CLL (U-CLL) was enriched in only one gene set, termed CLLUNMUT-1, while mutated CLL (M-CLL) was only enriched in CLLMUT-1. CD38high and CD38low subsets were similarly enriched in these two gene sets, with 4 additional gene sets in the CD38high group, including MYD88UP-4 and IFN-2. Of the 50 significantly enriched gene sets in the Ki-67high group, 17 relate to signaling pathways, 16 to cellular differentiation, 6 to cellular processes, 4 to transcription factor targets, and the remaining 7 relate to cancer. Of these, the percentage of the signaling component is up 13% from its representation in the original Staudt library. The top 5 gene sets enriched in the Ki-67high group are: upregulated U-CLL compared to M-CLL (CLLUNMUT-1), myeloid tissue compared to other tissues (MYELOID-1), T cell cytokine induced proliferation (TCYTUP-8), BCR crosslinking CLL B cells (CLLBCRUP-1) and BDCA4+ dendritic cells compared to other hematopoietic cells (DC-1). The total number of genes enriched in these 50 sets is 769, with 217 genes shared in two or more gene sets. Twenty genes were enriched in the CLL BCR signature, CLLBCRUP-1 [Herishanu Y, et al. Blood 2011]. Of these, WARS, IRF4, MX1, OAS1, and NAMPT are also enriched in the T cell cytokine induced and T cell activation signatures. Only one gene set was enriched in the Ki-67low group, CLLMUT-1, upregulated in M-CLL compared to U-CLL. CD274 (PD-L1) was consistently elevated in the Ki-67low group in all the patients, irrespective of IGHV mutation status. Discussion: The observed GSEA profiles in Ki-67high patients correlated with gene signatures biased towards BCR signaling, signal transduction, and hematopoietic cancer, consistent with the Ki-67high group containing more (recently) proliferating cells influenced at least in part by BCR signaling. The profiles also suggest that additional cells (T lymphocytes and dendritic cells) may be involved. It is notable these gene sets were not observed for CLL patients subgrouped by IGHV mutation status or by CD38, and that these other subsets did not show as pronounced a distinction by GSEA profiling. Disclosures: No relevant conflicts of interest to declare.

IDENTIFICATION OF DEREGULATED PATHWAYS IN METASTATIC RENAL CELL CARCINOMA USING GENE SET ENRICHMENT ANALYSIS (GSEA)

2009 ◽  
Vol 181 (4S) ◽  
pp. 37-37
Author(s):  
Alexander Buchner ◽  
Mirna Castro ◽  
Anja Hennig ◽  
Gerald Assmann ◽  
Christian G. Stief ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Gene Set
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