scholarly journals Genetic alterations associated with malignant transformation of sporadic vestibular schwannoma

2021 ◽  
Author(s):  
Aril Løge Håvik ◽  
Ove Bruland ◽  
Hrvoje Miletic ◽  
Lars Poulsgaard ◽  
David Scheie ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Malignant Transformation ◽  
Vestibular Schwannoma ◽  
Copy Number ◽  
Genetic Alterations ◽  
Whole Genome ◽  
Nerve Sheath Tumor ◽  
Copy Number Aberrations ◽  
Mutational Signature ◽  
Post Radiation

Abstract Introduction Malignant peripheral nerve sheath tumor of the vestibulocochlear nerve (VN-MPNST) is exceedingly rare and carries a poor prognosis. Little is known about its underlying genetics and in particular the process of malignant transformation. There is an ongoing debate on whether the transformation is initiated by ionizing radiation. We present here the analysis and comparison of two post-radiation VN-MPNST and one undergoing spontaneous transformation. Methods Four tumors from three patients (radiation-naïve vestibular schwannoma before (VS) and after (VN-MPNST) malignant transformation in addition to two post-radiation VN-MPNST) were subjected to DNA whole-genome microarray and whole-exome sequencing and tumor-specific mutations were called. Mutational signatures were characterized using MuSiCa. Results The tumor genomes were characterized predominantly by copy-number aberrations with 36–81% of the genome affected. Even the VS genome was grossly aberrated. The spontaneous malignant transformation was characterized by a near-total whole-genome doubling, disappearance of NF2 mutation and new mutations in three cancer-related genes (GNAQ, FOXO4 and PDGFRB). All tumors had homozygous loss of the tumor suppressor CDKN2A. Neither mutational signature nor copy number profile was associated with ionizing radiation. Conclusion The VN-MPNST genome in our cases is characterized by large copy-number aberrations and homozygous deletion of CDKN2A. Our study demonstrates a VS with genetic alterations similar to its malignant counterpart, suggesting the existence of premalignant VS. No consistent mutational signature was associated with ionizing radiation.

An exhaustive algorithm for detecting copy number aberrations and large structural variants in whole-genome, mate-pair sequencing data.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e22171-e22171
Author(s):  
Yan W. Asmann ◽  
Chen Wang ◽  
Brian M. Necela ◽  
Xianfeng Chen ◽  
Jean-Pierre A. Kocher ◽  
...  
Keyword(s):  
Copy Number ◽  
Whole Genome ◽  
Structural Variants ◽  
Sequencing Data ◽  
Copy Number Aberrations ◽  
Mate Pair

scholarly journals COMP-15. MOLECULAR AND CLONAL EVOLUTION IN RECURRENT METASTATIC GLIOSARCOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi64-vi64
Author(s):  
Kevin Anderson ◽  
Aaron Tan ◽  
Jonathon Parkinson ◽  
Michael Back ◽  
Marina Kastela ◽  
...  
Keyword(s):  
Copy Number ◽  
Clonal Evolution ◽  
Genetic Alterations ◽  
World Health ◽  
Surrounding Tissue ◽  
Driver Mutations ◽  
Whole Genome ◽  
Intracranial Tumors ◽  
First Recurrence ◽  
Extracranial Metastases

Abstract Gliosarcoma, a World Health Organization grade IV glioma, is a rare variant of glioblastoma (GBM) that contains distinct glial and mesenchymal components. Histologically, the glial component matches criteria for glioblastoma, and both components share genetic alterations common to GBM. Though GBM are known to strongly infiltrate surrounding tissue, extracranial metastases are rare, and the underlying mechanisms are still poorly understood. We present a rare case of a 37-year-old woman who was initially diagnosed with IDH wild-type gliosarcoma in the frontal lobe and later developed two local recurrences and extracranial metastases to the vertebral and pelvic bones. In order to understand the clonal relationships between four tumor instances and the origin of metastasis, we performed whole genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared mutational and copy number profiles and inferred tumor clonal phylogeny. The tumors harbored shared GBM alterations including TP53, NF1, and RB1 mutations and CDKN2A deletion. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profiles, but contrasting evidence regarding the origin of the metastasis. The metastasis was most similar to the second recurrence with respect to mutational signatures, reflected in the activity of signatures associated with defective DNA mismatch repair not observed in the primary or first recurrent tumor. The metastasis was most similar to the first recurrence with respect to copy number profile; both samples displayed widespread amplifications indicative of whole genome doubling. Results of subclonal reconstruction suggested that the second recurrent and metastatic tumors originated from more than one clone and developed subclone-specific driver mutations. The branching phylogeny and copy number profiles suggest the metastasis was largely derived from the first recurrence. This is the first analysis of clonal evolution of extracranial metastasis in gliosarcoma and highlights alterations driving aggressive GBM progression.

scholarly journals Hidden DNA Copy Number Alterations and Mutations in IKZF1, TP53, CRLF2 and JAK2 Genes Are Associated with a Poor Prognosis in B-Progenitor Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1082-1082
Author(s):  
Jesús María Hernández-Rivas ◽  
Maribel Forero ◽  
Cristina Robledo ◽  
Rocio Benito ◽  
María Hernández ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Integrative Analysis ◽  
Dna Copy Number ◽  
Copy Number Aberrations ◽  
Dna Copy Number Aberrations

Abstract Background: In B-progenitor acute lymphoblastic leukemia (B-ALL) the identification of additional genetic alterations associated with treatment failure is still a challenge. Aims: 1.To identify genomic gains and losses in B-ALL at the time of diagnosis and to correlate these abnormalities with the genetic characteristics and the patients outcome. 2.To assess the prevalence and prognostic impact of genetic lesions in IKZF1, TP53, CRLF2, IL7R, PAX5, JAK2 and LEF1 genes in B-ALL. Methods: A total of 215 B-ALL patients were eligible for this study. 115 (53.5%) had less than <18 years. In all cases oligonucleotide microarrays (aCGH) were carried out. For genetic gain and losses analysis, the NimbleGen CGH 12x135K array (Roche) was used. The data analysis was performed with GISTIC and aCGHweb software. In 118 of these cases (65 children and 53 adults), an integrative analysis of aCGH and NGS was performed to identify genetic lesions in genes associated with B-ALL: JAK2 (Exon 12-Exon 16), PAX5 (E2-E3), LEF1 (E2-E3), CRLF2 (E6), IL7R (E5), IKZF1 (E2-E8) and TP53 (E4-E11). The 454 GS Junior system (Roche) was used. The variant analysis was performed using Amplicon Variant Analyzer (AVA-Roche 454) and Sequence Pilot (JSI Medical Systems) software. Results: DNA copy number aberrations (CNAs) were observed in 96.5% of cases. Gains on chromosomes 4 (10%), 6 (10%), 10 (12%), 14 (13%), 21 (31%) and X (18%) were more common in children, whereas losses in 7p (13%) and 9p21 (24%) were frequent in adults. In children, gains on chromosomes 6, 10, 14q, 17, 18, 21 and X were associated with longer overall survival (OS) while loss on 7p and 17p were associated with shorter OS in adults (Table 1). The integrative analysis of aCGH and NGS showed that 60% of patients carried at least one alteration (deletion and/or mutation) in the seven genes analyzed. Focal deletions were common in IKZF1, CRLF2, PAX5, and LEF1 genes while broad deletions were more frequent in TP53, JAK2 and IL7R. Forty-one percent of patients harbored IKZF1 alterations (IKZF1+), 22.9% in PAX5, 18.6% in JAK2 and 11% had TP53 or CRLF2 alterations. LEF1 and IL7R genomic lesions were only present in 4.2% and 2.5% of the B-ALL, respectively. JAK2 and CRLF2 mutations were associated (p=0.01). Moreover abnormalities in IKZF1+ were associated with alterations in JAK2 (p=0.004), TP53 (p=0.04) and PAX5 (p=0.03). The presence of alterations was most frequent in high-risk (HR) B-ALL (38% vs 18%, p=0.02), although 8% low-risk (LR) childhood patients showed genetic alterations. Fourteen B-ALL patients carried mutations in TP53, CRLF2 and/or JAK2 genes: all of them were Ph-, and 11 were classified as HR. Of note, 3 cases were children. In the HR group the presence of mutation in TP53, CRLF2 and/or JAK2 was related to a shorter OS (3-year OS: 56% vs. 36%; P=0.034) and event-free survival (3-year EFS: 56% vs. 11%; P<0.002) (Figure 1), due to an increased cumulative incidence of relapse (3-year CIR: 38% vs. 88%; P<0.004). The presence of IKZF1 alterations stratified HR-Ph- B-ALL cases. Thus HR-Ph- patients with normal IKZF1 were associated with longer EFS compared to HR-Ph- B-ALL IKZF1+ (3-year EFS: 60% vs. 33%; P=0.005) (Figure 2). The presence of IKZF1 deletion was associated with shorter EFS (89% vs. 67%, P= 0.04) and increased CIR (3-year CIR: 12% vs. 33%; P=0.05) in children. Summary/Conclusions: CNAs are frequent in B-ALL and are associated with genetic subtype, age and overall survival. The integrative analysis by aCGH and NGS techniques demonstrated that alterations in IKZF1 gene and mutations in TP53, CRLF2 and/or JAK2 genes could stratify high-risk Ph- B-ALL patients. Subvention:FP7/2007-13, Nº306242-NGS-PTL; HUS272U13, JCyL,Consejería de Educación; BIO/SA31/13 Gerencia Regional de Salud, SACYL, Spain Table 1. DNA copy number aberrations (CNAs) associated with overall survival in 215 B-ALL patients Association CNA n Median (months) P value Short overall survival 7p-ChildrenAdults 19613 9615 0.05 17p-ChildrenAdults 1257 694 0.029 +19ChildrenAdults 351421 Not reached10 0.001 22q+ChildrenAdults 261214 Not reached7 <0.0001 Longoverall survival +6ChildrenAdults 26197 Not reached7 <0.0001 +10ChildrenAdults 25196 Not reached7 0.001 +14qChildrenAdults 26188 Not reached4 <0.0001 +17ChildrenAdults 24177 Not reached60 0.012 +18ChildrenAdults 25187 Not reachedNot reached <0.0001 21q+ChildrenAdults 473116 Not reached8 <0.0001 XChildrenAdults 522725 Not reached9 <0.0001 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Detection of copy number aberrations in cholangiocarcinoma using shallow whole genome sequencing of plasma DNA.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 293-293 ◽  
Author(s):  
Maria Farooq ◽  
Jan B. Egan ◽  
Bradon McDonald ◽  
Havell Markus ◽  
Tania Contente-Cuomo ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Whole Genome ◽  
Sequencing Data ◽  
Plasma Dna ◽  
Copy Number Aberrations ◽  
Ctdna Analysis ◽  
Tumor Genotyping

293 Background: Cholangiocarcinoma (CCA) is a deadly cancer with ~20% five year survival. Obtaining tissue to confirm diagnosis of CCA is often challenging. This also limits the use of tumor genotyping that could guide potential molecularly targeted treatment (such as FGFR inhibitors for a subset of cases). We investigated whether circulating tumor DNA (ctDNA) analysis in plasma is feasible for noninvasive tumor genotyping in patients with advanced CCA. Methods: We collected and processed plasma samples for ctDNA analysis from 17 patients with CCA at presentation and from 11 healthy volunteers. Following cell-free DNA extraction and quality assessment using digital PCR, we performed low-pass, shallow whole genome sequencing (sWGS). We analyzed sequencing data to identify copy number aberrations and quantify tumor fraction in plasma using recently published computational approaches. Results: Median total cfDNA concentration in patients with CCA was 7,003 genome equivalents (GEs)/mL plasma (range: 1,512- 107,707 GEs/mL) and significantly higher than healthy volunteers (two tailed t-test p < 0.04, median: 1,658 GEs/mL, range: 661-4,938 GEs/mL). We successfully sequenced all tumor libraries, generating a median of 173 million paired-end reads. ctDNA was detectable in 10/17 samples using sWGS. In these 10 samples, median tumor fraction in plasma DNA was 7.1% (range: 3.9%-44.6%). We found recurrent copy number aberrations expected in CCA including 1q gain in 80%, 7p gain in 50%, 1p loss in 70% and 3p loss in 50% of cases. Conclusions: ctDNA analysis for noninvasive tumor genotyping is feasible in patients with advanced cholangiocarcinoma. On-going work is focused on expanding these results using targeted and whole-exome sequencing.

scholarly journals Unravel Inter-Tumor and Intra-Tumor Heterogeneity of Digitally Sorted Single Hodgkin and Reed Sternberg Cells Using Genome-Wide Copy Number Profiling

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1568-1568
Author(s):  
Chiara Mangano ◽  
Petrini Edoardo ◽  
Marianna Garonzi ◽  
Rossana Lanzellotto ◽  
Francesca Marzia Papadopulos ◽  
...  
Keyword(s):  
Copy Number ◽  
Tumor Heterogeneity ◽  
Genetic Alterations ◽  
Target Cells ◽  
Whole Genome ◽  
Dependent Manner ◽  
Malignant Cells ◽  
Copy Number Alterations ◽  
Immune Infiltrate ◽  
Genome Wide

Abstract Introduction Immune-checkpoint blockade has emerged as an effective therapeutic strategy in solid tumor and in hematologic malignancies, including classical Hodgkin Lymphoma (cHL). cHL represents about 11% of all malignant lymphoma and it is generally highly curable with standard frontline therapies, although about 20% of the patients will relapse or become refractory after initial treatment. The hallmark of cHL is the presence of malignant Hodgkin and Reed-Sternberg Cells (HRS) that represent only a small fraction (about 1%) of the surrounding heterogeneous immune infiltrate. Despite this extensive inflammatory microenvironment, HRS are able to escape immune surveillance using several mechanisms, including the overexpression of PD-1 ligands (PD-Ls) that bind PD-1 on reactive T-cells, inhibiting their activity and proliferation and causing ultimately T-cell exhaustion. The PD-Ls expression is upregulated in a dose-dependent manner by copy number alterations of chromosome 9p24.1, a locus encoding for PD-L1/PD-L2 as well as JAK2, which further enhances PD-Ls expression through JAK2/STAT pathway. Here we present a method for the isolation and the genetic characterization of single purified HRS, which overcomes the limitations posed by the low tumor cellularity of cHL biopsies and gives an estimation of inter-tumor and intra-tumor heterogeneity which may be useful to guide immune treatment selection. Methods FFPE tissue sections from 4 cHL patients were dissociated down to single-cell suspension and stained using anti-CD30 and anti-PD-L1 antibodies. Since CD30 is not expressed exclusively by malignant cells, beyond the positivity to CD30 and PD-L1 HRS were selected according to morphological criteria, such as cell size and the presence of nuclei with ploidy higher than the surrounding lymphocytes. DEPArray™ NxT system (Menarini Silicon Biosystems) was used to isolate single target cells. After recovery, single cells were whole genome amplified (Ampli1™ WGA, Menarini Silicon Biosystems), and genome-wide copy-number alterations (CNAs) profiles were obtained using Ampli1™ LowPass kits (Menarini Silicon Biosystems) on Illumina® and Ion Torrent™ platforms. Results For each patient, at least 8 HRS cells and infiltrating lymphocytes were identified and isolated from lymphoid tissue using DEPArray™ NxT system. Copy-number analyses of recovered cells allowed us to precisely discriminate HRS, characterized by extensive gains and losses, from non-tumor cells, showing flat profiles as expected (Fig.1). Ploidy of HRS was automatically determined, based on best-fitting of profiles with underlying copy number levels. Hierarchical clustering showed that some alterations are highly conserved among patients, e.g. the region containing PD-L1/PD-L2/JAK2 has several copy gains in the majority of malignant cells. Interestingly, these alterations show high variable copy-number levels between different HRS even in the same patient, ranging from few copy-gains to amplifications, suggesting some level of heterogeneity. Different CNAs are also detected in regions containing genes belonging to pathways already known to be altered in cHL, like REL/NFKB and JAK/STAT pathways, which may be involved in the constitutive activation of proliferative and antiapoptotic phenotype of HRS. Conclusion Single HRS sorting combined with low-pass whole genome sequencing offer a valuable tool to uncover genetic alterations hidden by the massive cHL immune infiltrate and to estimate inter-tumor and intra-tumor heterogeneity in cHL patients. Considering that PD-Ls locus amplifications are associated with advanced stages of the disease and with a shorter progression free survival, the analysis of purified HRS could be helpful for patient stratification for the adoption of immune therapy. Disclosures Mangano: Menarini Silicon Biosystems: Employment. Edoardo:Menarini Silicon Biosystems: Employment. Garonzi:Menarini Silicon Biosystems: Employment. Lanzellotto:Menarini Silicon Biosystems: Employment. Papadopulos:Menarini Silicon Biosystems: Employment. Bolognesi:Menarini Silicon Biosystems: Employment. Buson:Menarini Silicon Biosystems: Employment. Ferrarini:Menarini Silicon Biosystems: Employment. Forcato:Menarini Silicon Biosystems: Employment. Fontana:Menarini Silicon Biosystems: Employment. Ceccolini:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Fabbri:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Fici:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Gallerani:Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS: Employment. Simonelli:Menarini Silicon Biosystems: Employment. Medoro:Menarini Silicon Biosystems: Employment. Manaresi:Menarini Silicon Biosystems: Employment.

scholarly journals Landscape of Genetic Alterations in Adult T-Cell Leukemia/Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 75-75
Author(s):  
Keisuke Kataoka ◽  
Yasunobu Nagata ◽  
Akira Kitanaka ◽  
Yasushi Totoki ◽  
Jun-ichirou Yasunaga ◽  
...  
Keyword(s):  
T Cell ◽  
Copy Number ◽  
Genetic Alterations ◽  
Whole Genome ◽  
T Cell Leukemia ◽  
Copy Number Alterations ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Lymphoid Malignancies ◽  
Human T Cell

Abstract Adult T-cell leukemia/lymphoma (ATL) is a distinct form of peripheral T-cell lymphoma, which is etiologically associated with human T-cell leukemia virus type 1 (HTLV-1) infection during early infancy. Although HTLV-1 can effectively immortalize human T cells, there is a long latency period of ~50 years before the onset of ATL, suggesting that HTLV-1 infection alone may be insufficient for the development of ATL, but additional acquired genetic events that accumulate during the later life are essential for the development of ATL. However, such somatic alterations underlying the pathogenesis of ATL have not been fully elucidated. To obtain a complete registry of genetic alterations in ATL, we performed an integrated genetic study, in which whole-genome/exome and RNA sequencing (RNA-seq) was performed together with array-based methylation and genomic copy number analysis among a cohort of 50 paired ATL samples, followed by extensive validation using targeted deep sequencing of detected mutations in > 400 follow-up samples. Compared with other lymphoid malignancies, ATL cells carried higher numbers of mutations, copy number alterations, and rearrangements than in other lymphoid malignancies, suggesting the presence of global genomic instability in ATL. In addition to previously reported mutational targets in ATL (TP53,TCF8, and FAS) and known targets frequently mutated in other lymphoid malignancies (CARD11, GATA3, IRF4, POT1, and RHOA), we identified a variety of highly recurrent mutations affecting previously unknown mutational targets, many of which are involved in T-cell development, activation and migration, immunosurveillance, and transcriptional regulation. Molecular and functional analysis using human T-cell leukemia cell lines showed that some of these novel mutations actually augment T-cell receptor signaling, validating their biological significance in ATL. A comparison of mutations among disease subtypes revealed that several subtype-specific mutations, including TP53, CD58, IRF4 and TBL1XR1 mutations in acute and lymphoma types, and STAT3mutation in chronic and smoldering types, suggesting that different oncogenic mechanisms underlie different ATL subtypes. Furthermore, ATL cells had a distinct pattern of copy number changes and genomic rearrangements. Interestingly, their gene targets showed a significant overlap to mutational targets. Surprisingly, somatic focal deletions involving the 14q31.1 locus were observed in all the cases examined by whole-genome sequencing and therefore are thought to uniquely characterize ATL genomes, although their gene targets remained to be identified. Like other regions also frequently deleted in ATL, such as 7q31.1 and 1p21.3 loci, these deletions were thought to reflect high levels of genetic instability. Finally and conspicuously, pathway analysis revealed that multiple genes involved in the Tax interactome were systematically altered in ATL, although Tax itself underwent gene silencing in most cases. These data suggested that ATL cells can escape from cytotoxic T-lymphocytes by silencing immunogenic Tax expression, while developing alternative oncogenic mechanisms through acquiring somatic mutations or copy number alterations in the Tax-related pathway. Our findings suggest that deregulated T-cell functionalities caused by genetic alterations, especially those associated with HTLV-1 Tax oncoprotein, are central to ATL pathogenesis, and provide a novel clue to contrive new diagnostics and therapeutics for this intractable disease. Disclosures No relevant conflicts of interest to declare.

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