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.

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 Moving Next-Generation Sequencing into the Clinic

2021 ◽  
Vol 42 (03) ◽  
pp. 221-228
Author(s):  
Omshree Shetty ◽  
Mamta Gurav ◽  
Prachi Bapat ◽  
Nupur Karnik ◽  
Gauri Wagh ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnostics ◽  
Single Gene ◽  
Tertiary Care ◽  
Genetic Alterations ◽  
Next Generation ◽  
Pathology Laboratory ◽  
Set Up ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

AbstractWith an advancement in the field of molecular diagnostics, there has been a profound evolution in the testing modalities, especially in the field of oncology. In the past decade, sequencing technology has evolved drastically with the advent of high-throughput next-generation sequencing (NGS). Subsequently, the single-gene tests have been replaced by multigene panel-based assays, deep sequencing, massively parallel whole genome, whole-exome sequencing, and so on. NGS has provided molecular diagnostics professionals a wonderful tool to explore and unearth the genetic alterations, underpinning the pathophysiology of the disease. However, this development has posed new challenges which consist of the following; understanding the technology, types of platforms available, various sequencing strategies, bioinformatics and data analysis algorithm, reporting of various variants, and validation of assays and overall for developing NGS assay for clinical utility. The challenges involved sometimes impede development of these high-end assays in laboratories. The present article provides a broad overview of our journey in setting up the NGS assay in a molecular pathology laboratory at a tertiary care oncology center. We hereby describe various important points and steps to be followed while working on the NGS setup, right from its inception to final drafting of the reports, with inclusion of various validation steps. We aim at providing a beginner’s guide to set up NGS assays in the laboratory using recommended best practices and various international guidelines.

Receptor tyrosine kinase gene amplification is predictive of intraoperative seizures during glioma resection with functional mapping

2020 ◽  
Vol 132 (4) ◽  
pp. 1017-1023 ◽  
Author(s):  
Bryan D. Choi ◽  
Daniel K. Lee ◽  
Jimmy C. Yang ◽  
Caroline M. Ayinon ◽  
Christine K. Lee ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Univariate Analysis ◽  
Tumor Resection ◽  
Tumor Grade ◽  
Molecular Data ◽  
Genetic Alterations ◽  
Functional Mapping ◽  
Chi Square ◽  
Kinase Gene ◽  
Glioma Resection

OBJECTIVEIntraoperative seizures during craniotomy with functional mapping is a common complication that impedes optimal tumor resection and results in significant morbidity. The relationship between genetic mutations in gliomas and the incidence of intraoperative seizures has not been well characterized. Here, the authors performed a retrospective study of patients treated at their institution over the last 12 years to determine whether molecular data can be used to predict the incidence of this complication.METHODSThe authors queried their institutional database for patients with brain tumors who underwent resection with intraoperative functional mapping between 2005 and 2017. Basic clinicopathological characteristics, including the status of the following genes, were recorded: IDH1/2, PIK3CA, BRAF, KRAS, AKT1, EGFR, PDGFRA, MET, MGMT, and 1p/19q. Relationships between gene alterations and intraoperative seizures were evaluated using chi-square and two-sample t-test univariate analysis. When considering multiple predictive factors, a logistic multivariate approach was taken.RESULTSOverall, 416 patients met criteria for inclusion; of these patients, 98 (24%) experienced an intraoperative seizure. Patients with a history of preoperative seizure and those treated with antiepileptic drugs prior to surgery were less likely to have intraoperative seizures (history: OR 0.61 [95% CI 0.38–0.96], chi-square = 4.65, p = 0.03; AED load: OR 0.46 [95% CI 0.26–0.80], chi-square = 7.64, p = 0.01). In a univariate analysis of genetic markers, amplification of genes encoding receptor tyrosine kinases (RTKs) was specifically identified as a positive predictor of seizures (OR 5.47 [95% CI 1.22–24.47], chi-square = 5.98, p = 0.01). In multivariate analyses considering RTK status, AED use, and either 2007 WHO tumor grade or modern 2016 WHO tumor groups, the authors found that amplification of the RTK proto-oncogene, MET, was most predictive of intraoperative seizure (p < 0.05).CONCLUSIONSThis study describes a previously unreported association between genetic alterations in RTKs and the occurrence of intraoperative seizures during glioma resection with functional mapping. Future models estimating intraoperative seizure risk may be enhanced by inclusion of genetic criteria.

scholarly journals Treatment-Free Remission—A New Aim in the Treatment of Chronic Myeloid Leukemia

2021 ◽  
Vol 11 (8) ◽  
pp. 697
Author(s):  
Paulina Kwaśnik ◽  
Krzysztof Giannopoulos
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Immune Surveillance ◽  
Gene Transcript ◽  
Clinical Relapse ◽  
Eligibility Criteria ◽  
Treatment Free Remission ◽  
Next Generation Sequencing Ngs ◽  
Specific Symptoms

Tyrosine kinases inhibitors (TKIs) revolutionized chronic myeloid leukemia (CML) treatment for many years, prolonging patients’ life expectancy to be comparable to age-matched healthy individuals. According to the latest the European LeukemiaNet (ELN) recommendations, CML treatment aims to achieve long-term remission without treatment (TFR), which is feasible in more than 40% of patients. Nearly all molecular relapses occur during the first 6 months after TKI withdrawal and do not progress to clinical relapse. The mechanisms that are responsible for CML relapses remain unexplained. It is suggested that maintaining TFR is not directly related to the total disposing of the gene transcript BCR-ABL1, but it might be a result of the restoration of the immune surveillance in CML. The importance of the involvement of immunocompetent cells in the period of TKI withdrawal is also emphasized by the presence of specific symptoms in some patients with “withdrawal syndrome”. The goal of this review is to analyze data from studies regarding TFRs in order to characterize the elements of the immune system of patients that might prevent CML molecular relapse. The role of modern droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing (NGS) in better identification of low levels of BCR-ABL1 transcripts was also taken into consideration for refining the eligibility criteria to stop TKI therapy.

scholarly journals LGG-31. CHARACTERIZING TEMPORAL GENOMIC HETEROGENEITY IN PEDIATRIC LOW GRADE GLIOMAS: ANALYSIS OF AN EXPANDED MULTI-INSTITUTIONAL COHORT WITH 101 PAIRED TUMOR SAMPLES

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii372-iii372
Author(s):  
Margot A Lazow ◽  
Austin Schafer ◽  
Mariko D DeWire-Schottmiller ◽  
Adam Lane ◽  
Daniel R Boué ◽  
...  
Keyword(s):  
Genetic Alterations ◽  
Rapid Progression ◽  
Low Grade ◽  
Valuable Insight ◽  
Histologic Diagnosis ◽  
Low Grade Gliomas ◽  
Genomic Landscape ◽  
Cdkn2a Deletion ◽  
Diagnostic Biopsy ◽  
Over Time

Abstract INTRODUCTION Recent discoveries have provided valuable insight into the genomic landscape of pediatric low grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. METHODS Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and exome analyses were performed on paired tumor samples from primary diagnostic and subsequent surgeries. RESULTS 101 tumor samples from 48 patients (43 with 2 specimens, 5 with 3 specimens) from 3 institutions underwent testing. BRAF fusion and BRAFV600E status were conserved in 100% and 97% of paired specimens, respectively. No loss or gain of IDH1 mutations or FGFR1, NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. CDKN2A deletions were acquired in 7 patients (including 3 who received chemotherapy [2 with temozolomide] and 1 who received radiation), and were associated with a trend toward shorter time to progression (median: 5.5 vs. 13.0 months [p=0.08]). CONCLUSIONS Most targetable genetic alterations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or radiation. However, CDKN2A deletion acquisition was demonstrated and may define a higher risk group. Given potential for targeted therapies for tumors acquiring CDKN2A deletions, performing a biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.

Distant metastases from an originally diagnosed melanoma in situ primary tumor

2021 ◽  
Author(s):  
Shoshana Zhang ◽  
Kristan Schiele ◽  
Clay J. Cockerell ◽  
Roopal Bhatt
Keyword(s):  
Primary Tumor ◽  
Distant Metastases ◽  
Melanoma In Situ

Molecular defects in thyroid carcinomas: Role of the RET oncogene in thyroid neoplastic transformation

1995 ◽  
Vol 133 (5) ◽  
pp. 513-522 ◽  
Author(s):  
Massimo Santoro ◽  
Michele Grieco ◽  
Rosa Marina Melillo ◽  
Alfredo Fusco ◽  
Giancarlo Vecchio
Keyword(s):  
Tyrosine Kinases ◽  
Point Mutations ◽  
Neoplastic Transformation ◽  
Thyroid Neoplasms ◽  
Genetic Alterations ◽  
Thyroid Carcinomas ◽  
Molecular Defects ◽  
Genetic And Environmental Factors ◽  
Definition Of

Santoro M, Grieco M, Melillo RM, Fusco A, Vecchio G. Molecular defects in thyroid carcinomas. Role of the RET oncogene in thyroid neoplastic transformation. Eur J Endocrinol 1995;133:513–22. ISSN 0804–4643 Tumors are believed to arise as a result of an accumulation of mutations in critical genes involved in the control of cell proliferation. Thyroid neoplasms represent a good model for studying the role of these mutations in epithelial cell multistep carcinogenesis because they comprise a broad spectrum of lesions with different degrees of malignancy. Recent reports have described the involvement of specific genetic alterations in different types of thyroid neoplasms. Papillary carcinomas are characterized by the activation of the receptor tyrosine kinases RET and TRK-A proto-oncogenes. Ras point mutations are frequently observed in tumors with follicular histology and a high prevalence of p53 point mutations have been found in anaplastic carcinomas. A definition of molecular defects characterizing thyroid tumors will be helpful in establishing sensitive and specific detection strategies and, in addition, to define genetic and environmental factors important for their pathogenesis. Giancarlo Vecchio, Dipartimento di Biologia e Patologia Cellulare e Molecolare "L, Califano", Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II", via S Pansini 5, 80131 Napoli, Italy

scholarly journals High-Throughput Approaches onto Uncover (Epi)Genomic Architecture of Type 2 Diabetes

Genes ◽  
2018 ◽  
Vol 9 (8) ◽  
pp. 374 ◽  
Author(s):  
Anna Dziewulska ◽  
Aneta Dobosz ◽  
Agnieszka Dobrzyn
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
High Throughput ◽  
Target Genes ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genomic Landscape ◽  
A Genome ◽  
Next Generation Sequencing Ngs

Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. High-throughput approaches have opened a new avenue toward a better understanding of the molecular bases of T2D. A genome-wide association studies (GWASs) identified a group of the most common susceptibility genes for T2D (i.e., TCF7L2, PPARG, KCNJ1, HNF1A, PTPN1, and CDKAL1) and illuminated novel disease-causing pathways. Next-generation sequencing (NGS)-based techniques have shed light on rare-coding genetic variants that account for an appreciable fraction of T2D heritability (KCNQ1 and ADRA2A) and population risk of T2D (SLC16A11, TPCN2, PAM, and CCND2). Moreover, single-cell sequencing of human pancreatic islets identified gene signatures that are exclusive to α-cells (GCG, IRX2, and IGFBP2) and β-cells (INS, ADCYAP1, INS-IGF2, and MAFA). Ongoing epigenome-wide association studies (EWASs) have progressively defined links between epigenetic markers and the transcriptional activity of T2D target genes. Differentially methylated regions were found in TCF7L2, THADA, KCNQ1, TXNIP, SOCS3, SREBF1, and KLF14 loci that are related to T2D. Additionally, chromatin state maps in pancreatic islets were provided and several non-coding RNAs (ncRNA) that are key to T2D pathogenesis were identified (i.e., miR-375). The present review summarizes major progress that has been made in mapping the (epi)genomic landscape of T2D within the last few years.

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