scholarly journals Genomic Landscape of Angiosarcoma: A Targeted and Immunotherapy Biomarker Analysis

2021 ◽  
Author(s):  
Andrea Espejo-Freire ◽  
Andrew Elliot ◽  
Andrew Rosenberg ◽  
Philippos Apolinario Costa ◽  
Priscila Barreto Coelho ◽  
...  
Keyword(s):  
Tumor Mutation Burden ◽  
Entire Cohort ◽  
Immune Signature ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Mutation Burden ◽  
Biomarker Analysis ◽  
Next Generation Sequencing Ngs ◽  
Response Biomarkers ◽  
Generation Sequencing

We performed a comprehensive analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin. We aimed to describe the genomic landscape of AS in a cohort of 143 cases of AS profiled by Caris Life Sciences. Data of Next Generation Sequencing (NGS) with a 592 gene panel was available for the entire cohort. Fifty-three cases had data of Whole Exome Sequencing (WES) which we used to study the microenvironment phenotype. Immuno-therapy (IO) response biomarkers: Tumor Mutation Burden (TMB), Microsatellite Instability (MSI) and PD-L1 status were included. IO-response markers were present in 36.4% of the cohort and in 65% of head and neck AS (H/N-AS) (p<0.0001). H/N-AS cases had predominantly muta-tions in TP53 (50.0%, p=0.0004), POT1 (40.5%, p<0.0001) and ARID1A (33.3%, p=0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p<0.0001), HRAS (16.1%, p=0.0377), and PI3KCA (16.1%, p=0.2352). A microenvironment with a high immune signature, associated with better response to IO, was present in 13% of the cases. This signature was evenly distributed among different primary sites. We found that the molecular biology for AS varies significantly according to the primary site. Our findings can facilitate the design and optimiza-tion of therapeutic strategies for AS to overcome resistance to IO and targeted therapies.

scholarly journals Genomic Landscape of Angiosarcoma: A Targeted and Immunotherapy Biomarker Analysis

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4816
Author(s):  
Andrea P. Espejo-Freire ◽  
Andrew Elliott ◽  
Andrew Rosenberg ◽  
Philippos Apolinario Costa ◽  
Priscila Barreto-Coelho ◽  
...  
Keyword(s):  
Head And Neck ◽  
Genetic Alterations ◽  
Design And Optimization ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Mutation Burden ◽  
Biomarker Analysis ◽  
Next Generation Sequencing Ngs ◽  
Response Biomarkers ◽  
Ngs Data

We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.

Correlation of negative PD-L1 expression with TMB-H and MSI-H rates.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13162-e13162
Author(s):  
Jun Dong ◽  
Xiaoni Zhang ◽  
Hongyue Qu ◽  
Shifu Chen ◽  
Ziyang Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Cancer Colorectal ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Sequencing Library ◽  
Expression Evaluation ◽  
L1 Protein ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

e13162 Background: PD-L1 protein expression, tumor mutation burden (TMB) and microsatellite instability (MSI) are majorbiomarkers for PD-1/PD-L1 blockade therapy for solid tumors. We designed a study to evaluate the relevance of these biomarkers. Methods: From April 2018 to December 2018, 197 patients with lung cancer, colorectal cancer, andgastric cancer wereprospectivelyenrolled.Foreachpatient, afreshfrozentissuesampleor FFPE sample wascollected. Each sample was dividedinto3parts for next-generation sequencing (NGS), PD-L1 protein expression evaluation and MSI evaluation. The sequencing library was captured using a 605-gene panel and sequenced at~5,000×coverage.Mutationsinthe NGS datawereidentified,andTMB was then calculated. The PD-L1 protein expression was analyzedby immunohistochemistry, and the MSI was evaluated using a multiplex PCR comprising 5 loci(NR27, NR21, NR24, BAT25, and BAT26). Results: 18.78% (37/197) were detected with high PD-L1 expression (positive tumor cells ≥50%); 5.08% (10/197) ofpatientswere diagnosed as MSI-H; 4.06% (8/197) of patients had a TMB-H (TMB > 20 mutations/Mb). Among the 37 PD-L1 positive patients, only one patientwith TMB-Hwas detected, and 3patients were MSI-H. In contrast, among the 14 patients with PD-L1 expression less than 1%, 8patients (57.14%) were detected with TMB-H or MSI-H (3 with TMB-H only, 3 with MSI-H only, and 2 with both). In addition, among all the 10patients with MSI-H, 4patients had TMB-H, indicating that MSI-H may be partly associatedwith high TMB. Conclusions: From our preliminary result, PD-L1 protein expression negative patients tend to have higher rates of TMB-H and MSI-H. For patients with negative PD-L1 expression, it issuggested to evaluate its TMB level and MSI status. This study is ongoing, and more data will be collected to verify these findings.

Genomic landscape of angiosarcoma: A targeted and immunotherapy biomarker analysis of 143 patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11545-11545
Author(s):  
Andrea P. Espejo Freire ◽  
Andrew Elliott ◽  
Yamac Akgun ◽  
Philippos Costa ◽  
Maryam Alasfour ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitors ◽  
Therapy Response ◽  
Primary Tumor Site ◽  
Damage Repair ◽  
Genomic Landscape ◽  
Biomarker Analysis ◽  
Whole Transcriptome Sequencing ◽  
Next Generation Sequencing Ngs ◽  
Response Biomarkers

11545 Background: Targeted therapies for angiosarcoma (AS) patients have limited efficacy. Although significant responses to immunotherapy (IO-therapy) have been observed in cutaneous AS, its efficacy across all types of AS is not known. Herein, we describe genetic and molecular biomarkers of AS in order to propose potential therapeutic options. Methods: We retrospectively reviewed 143 AS tumors profiled by Next-Generation Sequencing (NGS) 592-gene panel (Caris Life Sciences,Irving, TX, USA). Whole transcriptome sequencing (WTS) was performed on 53 tumors. Mutations and copy number amplifications (CNAs) were analyzed and grouped by pathway. Biomarkers potentially associated with response to IO-therapy (TMB-High [≥10/Mb], MSI-High, and PD-L1 [IHC ≥ 2+ and 5%]) were also analyzed. AS subtypes based on primary tumor site were compared. P-values were corrected using a Benjamini & Hochberg method. Results: Sample median age was 67 (range 22-89), 61% were female, and 29% were classified as metastatic/recurrent. The most commonly mutated genes were TP53 (29%), ARID1A (17%), POT1 (16%), and ATRX (13%); MYC CNA was found in 23% of cases. IO-therapy markers were present in 36.4% of cases (TMB-High in 26%, PD-L1+ 21.8%, MSI-High 0.7%). Pathway alterations were detected in 86% of AS cases. By pathway, TP53 was altered in 31%, cell cycle 30%, DNA damage repair (DDR) 21%, RAS 18%, PI3K 15% and chromatin remodeling 14%. By site, head/neck (HN) AS had the highest rate of IO-therapy markers (65%, p < 0.05) [TMB-High (63%, p < 0.0001)], TP53 mutation (51%, p = 0.07), and POT1A mutation (41%, p < 0.01). MYC CNA was highest in breast (63%) and extremity (40%) AS (p < 0.0001). DDR alterations were present in 56% (p = 0.09) of cutaneous AS and ranged from 12-27% in other subtypes (not significant, NS). RAS and PI3K alterations ranged from 6-27% across all subtypes (NS). Conclusions: Our findings suggest differential angiosarcoma biology across primary sites. HN AS had more frequent markers of potential IO-therapy response, as well as DDR alterations. Next in frequency, we found ARID1A which is possibly associated with overactive EZH2, a target of tazemetostat. MYC amplification suggests a role targeting cell cycle via cyclin-dependent kinase or bromodomain inhibitors in breast and extremity ASs. Finally, RAS and PI3K are mutated in a low percentage of cases, explaining the limited benefit of tyrosine kinase inhibitors in AS. Future AS clinical trials should be designed with consideration of primary site, IO-therapy response biomarkers, and activated pathway.

Two Components of Variant Profiles in Primary Vaginal Carcinosarcoma via Next-Generation Sequencing and a Literature Review

2021 ◽  
pp. 106689692110379
Author(s):  
Rakan Kotoku ◽  
Shintaro Yanazume ◽  
Takafumi Kuroda ◽  
Yusuke Kobayashi ◽  
Ikumi Kitazono ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Vaginal Bleeding ◽  
Surgical Excision ◽  
Next Generation ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Aggressive Tumor ◽  
Post Menopausal ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Primary vaginal carcinosarcoma (VCS) is an extremely rare and aggressive tumor consisting of admixed malignant epithelial and mesenchymal elements. We report a case of VCS that was subjected to analysis by immunohistochemistry and next-generation sequencing (NGS). A 53-year-old woman with post-menopausal vaginal bleeding underwent surgical excision followed by concurrent chemoradiation. A well demarcated tumor was growing in a discontinuous fashion at a location some distance from both the cervix and vulva. Microscopically, the tumor consisted of adenocarcinoma components and sarcoma components consisting of a sheet-like growth of spindle-shaped cells, and we diagnosed this tumor as primary vaginal carcinosarcoma. NGS analysis of each component identified the following variants, TP53, PIK3CA, KRAS and FBXW7. A comparison of microsatellite instability (MSI) and tumor mutation burden (TMB) showed that within both tissues the sarcomatous components had a higher MSI and TMB than the carcinomatous components. This case supports “a monoclonal theory” with the genome profile being similar to other malignant mixed Müllerian tumors.

Exploration of Tumor Mutation Burden Combined with Immune Infiltrates in the Prognosis of Lung Adenocarcinoma

2021 ◽  
Author(s):  
Zhenyu Zhao ◽  
Boxue He ◽  
Qidong Cai ◽  
Pengfei Zhang ◽  
Xiong Peng ◽  
...  
Keyword(s):  
High Risk ◽  
Lung Adenocarcinoma ◽  
Clinical Application ◽  
Risk Group ◽  
High Risk Group ◽  
Immune Microenvironment ◽  
Tumor Mutation Burden ◽  
Immune Signature ◽  
Immune Infiltration ◽  
Mutation Burden

Abstract Background: Lung adenocarcinoma (LUAD) accounts for a majority of cancer-related deaths worldwide annually. A recent study shows that immunotherapy is an effective method of LUAD treatment, and tumor mutation burden (TMB) was associated with the immune microenvironment and affected the immunotherapy. Exploration of the gene signature associated with tumor mutation burden and immune infiltrates in predicting prognosis in lung adenocarcinoma in this study, we explored the correlation of TMB with immune infiltration and prognosis in LUAD.Materials and Methods: In this study, we firstly got mutation data and LUAD RNA-Seq data of the LUAD from The Cancer Genome Atlas (TCGA), and according to the TMB we divided the patients into high/low-TMB levels groups. The gene ontology (GO) pathway enrichment analysis and KOBAS-Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis were utilized to explore the molecular function of the differentially expressed genes (DEGs) between the two groups. The function enrichment analyses of DEGs were related to the immune pathways. Then, the ESTIMATE algorithm, CIBERSORT, and ssGSEA analysis were utilized to identify the relationship between TMB subgroups and immune infiltration. According to the results, Venn analysis was utilized to select the immune-related genes in DEGs. Univariate and Lasso Cox proportional hazards regression analyses were performed to construct the signature which positively associated with the immune infiltration and affected the survival. Finally, we verified the correlation between the signature and immune infiltration. Result: The exploration of the immune infiltration suggested that high-TMB subgroups positively associated with the high level of immune infiltration in LUAD patients. According to the TMB-related immune signature, the patients were divided into High/Low-risk groups, and the high-risk group was positively associated with poor prognostic. The results of the PCA analysis confirmed the validity of the signature. We also verified the effectiveness of the signature in GSE30219 and GSE72094 datasets. The ROC curves and C-index suggested the good clinical application of the TMB-related immune signature in LUAD prognosis. Another result suggested that the patients of the high-risk group were positively associated with higher TMB levels, PD-L1expression, and immune infiltration levels.Conclusion: In conclusion, our signature provides potential biomarkers for studying aspects of the TMB in LUAD such as TMB affected immune microenvironment and prognosis. This signature may provide some biomarkers which could improve the biomarkers of PD-L1 immunotherapy response and were inverted for the clinical application of the TMB in LUAD. LUAD male patients with higher TMB-levels and risk scores may benefit from immunotherapy. The high-risk patients along with higher PD-L1 expression of the signature may suitable for immunotherapy and improve their survival by detecting the TMB of LUAD.

Tumor Mutation Burden Computation in Two Pan-Cancer Precision Medicine Next-Generation Sequencing Panels

2020 ◽  
Vol 27 (10) ◽  
pp. 1553-1560 ◽  
Author(s):  
Yongqian Shu ◽  
Xiaohong Wu ◽  
Jia Shen ◽  
Dongdong Luo ◽  
Xiang Li ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Precision Medicine ◽  
Next Generation ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Pan Cancer ◽  
Generation Sequencing
Sign in / Sign up

Export Citation Format

Share Document