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.

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&lt;0.0001). H/N-AS cases had predominantly muta-tions in TP53 (50.0%, p=0.0004), POT1 (40.5%, p&lt;0.0001) and ARID1A (33.3%, p=0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p&lt;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.

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.

Genomic landscape and tumor mutation burden analysis of Chinese patients with sarcomatoid carcinoma of the head and neck

Oral Oncology ◽  
2021 ◽  
Vol 121 ◽  
pp. 105436
Author(s):  
Hai-bing Chen ◽  
Xiao-yang Gong ◽  
Wang Li ◽  
Dong-sheng Chen ◽  
Le-le Zhao ◽  
...  
Keyword(s):  
Head And Neck ◽  
Sarcomatoid Carcinoma ◽  
Chinese Patients ◽  
Tumor Mutation Burden ◽  
Genomic Landscape ◽  
Mutation Burden

scholarly journals MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas

2019 ◽  
Vol 3 (3) ◽  
pp. 375-383 ◽  
Author(s):  
Naema Nayyar ◽  
Michael D. White ◽  
Corey M. Gill ◽  
Matthew Lastrapes ◽  
Mia Bertalan ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Phylogenetic Analysis ◽  
Nervous System ◽  
B Cell ◽  
Central Nervous System Lymphoma ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Frequent Mutations

Abstract The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted MYD88 sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified MYD88 mutation in 67% (42 of 63) of patients, CDKN2A biallelic loss in 44% (16 of 36), and CD79b mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, CDKN2A), with few areas of amplification. CD79b mutations were associated with improved progression-free and overall survival. We did not identify amplification at the PD-1/PD-L1 loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified MYD88 mutation and CDKN2A loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of PD-L1 amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.

scholarly journals Genomic characteristics of invasive mucinous adenocarcinoma of the lung with multiple pulmonary sites of involvement

2021 ◽  
Author(s):  
Moonsik Kim ◽  
Jinha Hwang ◽  
Kyung A Kim ◽  
Sohyun Hwang ◽  
Hye-Jeong Lee ◽  
...  
Keyword(s):  
Interstitial Pneumonia ◽  
Mucinous Adenocarcinoma ◽  
Usual Interstitial Pneumonia ◽  
Dna Mismatch ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Process Signature ◽  
Invasive Mucinous Adenocarcinoma

AbstractInvasive mucinous adenocarcinoma (IMA) of the lung frequently presents with diffuse pneumonic-type features or multifocal lesions, which are regarded as a pattern of intrapulmonary metastases. However, the genomics of multifocal IMAs have not been well studied. We performed whole exome sequencing on samples taken from 2 to 5 regions in seven patients with synchronous multifocal IMAs of the lung (24 regions total). Early initiating driver events, such as KRAS, NKX2-1, TP53, or ARID1A mutations, are clonal mutations and were present in all multifocal IMAs in each patient. The tumor mutational burden of multifocal IMAs was low (mean: 1.13/mega base), but further analyses suggested intra-tumor heterogeneity. The mutational signature analysis found that IMAs were predominantly associated with endogenous mutational process (signature 1), APOBEC activity (signatures 2 and 13), and defective DNA mismatch repair (signature 6), but not related to smoking signature. IMAs synchronously located in the bilateral lower lobes of two patients with background usual interstitial pneumonia had different mutation types, suggesting that they were double primaries. In conclusion, genomic evidence found in this study indicated the clonal intrapulmonary spread of diffuse pneumonic-type or multifocal IMAs, although they can occur in multicentric origins in the background of usual interstitial pneumonia. IMAs exhibited a heterogeneous genomic landscape despite the low somatic mutation burden. Further studies are warranted to determine the clinical significance of the genomic characteristics of IMAs in expanded cohorts.

scholarly journals mTOR co-targeting strategies for head and neck cancer therapy

2017 ◽  
Vol 36 (3) ◽  
pp. 491-502 ◽  
Author(s):  
Zhiyong Wang ◽  
Juan Callejas Valera ◽  
Xuefeng Zhao ◽  
Qianming Chen ◽  
J. Silvio Gutkind
Keyword(s):  
Head And Neck ◽  
Mtor Inhibitors ◽  
Genetic Alterations ◽  
Mtor Inhibition ◽  
Experimental Systems ◽  
Genomic Landscape ◽  
New Findings ◽  
Effective Option ◽  
Immune Oncology ◽  
Anti Tumor Activity

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. There is an urgent need to develop effective therapeutic approaches to prevent and treat HNSCC. Recent deep sequencing of the HNSCC genomic landscape revealed a multiplicity and diversity of genetic alterations in this malignancy. Although a large variety of specific molecules were found altered in each individual tumor, they all participate in only a handful of driver signaling pathways. Among them, the PI3K/mTOR pathway is the most frequently activated, which plays a central role in cancer initiation and progression. In turn, targeting of mTOR may represent a precision therapeutic approach for HNSCC. Indeed, mTOR inhibition exerts potent anti-tumor activity in HNSCC experimental systems, and mTOR targeting clinical trials show encouraging results. However, advanced HNSCC patients may exhibit unpredictable drug resistance, and the analysis of its molecular basis suggests that co-targeting strategies may provide a more effective option. In addition, although counterintuitive, emerging evidence suggests that mTOR inhibition may enhance the anti-tumor immune response. These new findings raise the possibility that the combination of mTOR inhibitors and immune oncology agents may provide novel precision therapeutic options for HNSCC.

scholarly journals Molecular and clinical characteristics of primary pulmonary lymphoepithelioma-like carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20541-e20541
Author(s):  
Ying Fan ◽  
Qian Yun Shan ◽  
Jia Li Gong ◽  
Jing Qin ◽  
Hongyang Lu
Keyword(s):  
Clinical Characteristics ◽  
Genetic Alterations ◽  
Treatment Protocols ◽  
Barr Virus ◽  
Mutation Burden ◽  
Programmed Cell Death 1 ◽  
Mutation Profile ◽  
Promising Treatment ◽  
Epstein Barr ◽  
Next Generation Sequencing Ngs

e20541 Background: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is an extremely rare subtype of non-small cell lung cancer (NSCLC) and there are no established treatment protocols due to its rarity. At present there are only limited studies about the molecular and clinical characteristics of PPLELC and the results are often inconsistent. Methods: The study collected patients with PPLELC who were admitted to Zhejiang Cancer Hospital from 2009 to 2020 retrospectively. Next-generation sequencing (NGS) was performed to obtain a more comprehensive mutation profile of PPLELE, tumor mutation burden (TMB) level and the expression of programmed cell death 1 ligand 1(PD-L1) was detected for 7 patients. In addition, we review the studies concerning the immunotherapy of advanced PPLELC. Results: 18 patients diagnosed as PPLELC pathologically were collected. 71.4% (5/7) patients expressed PD-L1 (≥ 1%) and the median TMB was 2.5 mutations/Mb. TP53 (43%) and CYLD (43%) were the two most common mutations and other variants included LRIG1 (14%), PTPRT (14%), PPP2R2A (14%). 15 patients survived, 3 patients died and 1 patient was lost after a followed up time for 8.8 to 138 months. A total of 11 cases of advanced PPLELC patients who received immunotherapy were analyzed retrospectively and the disease control rate (DCR) was 90.9%. Conclusions: The prognosis of PPLELC is better than that of other NSCLC and immunotherapy may be a promising treatment to prolong the survival time of advanced PPLELC.Whether the immunotherapy efficacy of PPLELC can be predict by PD-L1 and TMB is worthy of further clinical research. CYLD genetic alterations may participate in Epstein-Barr virus (EBV) -mediated tumorigenesis in PPLELC and expected to provide a new therapeutic target.

scholarly journals Two progressed malignant phyllodes tumors of the breast harbor alterations in genes frequently involved in other advanced cancers

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Mattea Reinisch ◽  
Sherko Kuemmel ◽  
Elisabeth Breit ◽  
Ingo Theuerkauf ◽  
Hakima Harrach ◽  
...  
Keyword(s):  
Primary Tumor ◽  
Tyrosine Kinases ◽  
Distant Metastases ◽  
Genetic Alterations ◽  
Recurrent Tumor ◽  
Pathology Laboratory ◽  
Phyllodes Tumors ◽  
Prediction Tools ◽  
Genomic Landscape ◽  
Next Generation Sequencing Ngs

Abstract Background The genomic landscape of phyllodes tumors (PTs) of the breast is not well defined, especially in patients with advanced disease. To shed light on this topic, paired primary and progressed tumor samples from two patients with malignant PTs were subjected to next-generation sequencing (NGS) followed by functional analysis of genetic alterations using two prediction tools. Methods The DNA of both the primary tumor and distant metastases of Patient 1 and the primary and recurrent tumor of Patient 2 were subjected to molecular profiling. NGS with the FoundationOne® assay was performed in a commercial molecular pathology laboratory. Two in silico prediction tools were used to estimate the pathogenicity of indicated genetic alterations. Results In total, 38 genomic alterations were detected, of which 11 were predicted to be probably benign. In Patient 1, 14 aberrations were identified in the primary tumor and 17 in pulmonary metastases, 12 of which were identical. In the primary and recurrent tumor of Patient 2, 17 and 15 sequence variants, respectively, were found, with 13 overlapping findings. Affected genes included seven (TP53, TERT, APC, ARID1A, EGFR, KMT2D, and RB1) of the top 10 most frequently altered genes in other advanced cancer entities, as well as four actionable therapeutic targets (EGFR, KIT, PDGFRA, and BRIP1). Of note, seven genes coding for receptor tyrosine kinases were affected: three in Patient 1 and four in Patient 2. Several genes (e.g. EPHA3, EPHA7, and EPHB1) were shown to be altered for the first time in PTs. Conclusions The two progressed malignant PTs investigated here share some of the major genetic events occurring in other advanced cancers.

Molecular determinants of response and resistance to anti-PD-(L)1 blockade in patients with NSCLC profiled with targeted next-generation sequencing (NGS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9015-9015 ◽  
Author(s):  
Matthew David Hellmann ◽  
Francisco Sanchez-Vega ◽  
Konnor La ◽  
Hira Rizvi ◽  
Darragh Halpenny ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Clinical Benefit ◽  
Copy Number ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Mutation Burden ◽  
Targeted Ngs ◽  
Molecular Determinants ◽  
Next Generation Sequencing Ngs

9015 Background: Anti-PD-(L)1 therapy has revolutionized treatment for patients (pts) with NSCLC. We previously reported that non-synonymous tumor mutation burden (TMB) by whole exome sequencing associates with immunotherapy benefit. Targeted NGS is increasingly routine in clinical practice and may be a useful tool for predicting benefit to anti-PD-(L)1 blockade. Methods: Pts had advanced NSCLC treated with anti-PD-(L)1 (+/- aCTLA-4) therapy and profiling by hybrid-capture NGS of 341-468 genes (MSK-IMPACT). Efficacy assessed by RECIST v1.1; durable clinical benefit (DCB) defined as PR or SD > 6mo. TMB and copy number alteration burden (“fraction of genome altered”, FGA) were normalized by size of genome covered. Comparisons were also made to a cohort of all NSCLCs profiled by MSK-IMPACT (n = 1679). Results: Of 437 evaluable pts treated with anti-PD-(L)1, 197 (45%) had NGS profiling, of whom 30% had DCB. TMB was higher in those with DCB vs no DCB (mean 10.2 vs 7.1 SNV/MB, p = 0.02) and compared to all NSCLCs ( < 0.0001). DCB was more common and PFS was longer in pts with > vs < 85th percentile TMB of all NSCLCs (Odds ratio 2.3, 95% CI 1.1-4.9, p = 0.03; HR = 0.59, p = 0.004), but were similar when dichotomized at the 50th or 75th percentile. FGA was higher in pts with no DCB compared to all NSCLCs (p = 0.02). Molecular signatures related to deficient homologous-recombination-based DNA repair and smoking were more common in DCB vs no DCB (p = 0.042, p = 0.058) and vs all NSCLCs (p = 0.026, p = 0.01). Compared to all NSCLCs profiled by NGS, alterations in STK11and EGFRwere enriched in no DCB (p = 0.0008, p = 0.02). Alterations in JAK2and CD274(PD-L1) were uncommon (2.1%, 1.6%) but exclusively associated with no DCB. For a subset (n = 52) of these cases also profiled by whole exome sequencing, comparison with targeted NGS will be presented. Conclusions: In pts with NSCLC, targeted NGS profiling is a routinely available tool that can provide insight into predicting benefit with anti-PD-(L)1 therapy. Increased TMB associates with clinical benefit. Increased copy number alterations (FGA) and alterations in genes including STK11, JAK2, and CD274 may associate with resistance to anti-PD-(L)1 therapy.

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