scholarly journals Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

2019 ◽  
Vol 32 (4) ◽  
pp. 564-575 ◽  
Author(s):  
Nihal Kenawy ◽  
Helen Kalirai ◽  
Joseph J. Sacco ◽  
Sarah L. Lake ◽  
Steffen Heegaard ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Conjunctival Melanoma ◽  
Mutation Status

scholarly journals Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma

2016 ◽  
Vol 54 (3) ◽  
pp. 278-286
Author(s):  
J. Perez-Escuredo ◽  
A. Lopez-Hernandez ◽  
M. Costales ◽  
F. Lopez ◽  
S.P. Ares ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Copy Number ◽  
Genetic Alterations ◽  
Intestinal Type ◽  
Dust Exposure ◽  
Copy Number Alterations ◽  
A Genome ◽  
Sinonasal Adenocarcinoma ◽  
Gains And Losses ◽  
Microarray Cgh

Background: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Material and methods: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Results: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. Conclusion: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

scholarly journals Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

2018 ◽  
Author(s):  
Nitin Roper ◽  
Shaojian Gao ◽  
Tapan K. Maity ◽  
A. Rouf Banday ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Copy Number ◽  
Thymic Carcinoma ◽  
Patient Specific ◽  
Tumor Evolution ◽  
Copy Number Alterations ◽  
Immune Microenvironment ◽  
Mutation Status ◽  
Whole Exome ◽  
Rapid Autopsy ◽  
Insight Into

ABSTRACTElucidation of the proteogenomic evolution of metastatic tumors may offer insight into the poor prognosis of patients harboring metastatic disease. We performed whole-exome and transcriptome sequencing, copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of 37 lung adenocarcinoma (LUAD) and thymic carcinoma (TC) metastases obtained by rapid autopsy and found evidence of patient-specific, multi-dimensional heterogeneity. Extreme mutational heterogeneity was evident in a subset of patients whose tumors showed increased APOBEC-signature mutations and expression of APOBEC3 region transcripts compared to patients with lesser mutational heterogeneity. TP53 mutation status was associated with APOBEC hypermutators in our cohort and in three independent LUAD datasets. In a thymic carcinoma patient, extreme heterogeneity and increased APOBEC3AB expression was associated with a high-risk germline APOBEC3AB variant allele. Patients with CNA occurring late in tumor evolution had corresponding changes in gene expression and protein abundance indicating genomic instability as a mechanism of downstream transcriptomic and proteomic heterogeneity between metastases. Across all tumors, proteomic heterogeneity was greater than copy number and transcriptomic heterogeneity. Enrichment of interferon pathways was evident both in the transcriptome and proteome of the tumors enriched for APOBEC mutagenesis despite a heterogeneous immune microenvironment across metastases suggesting a role for the immune microenvironment in the expression of APOBEC transcripts and generation of mutational heterogeneity. The evolving, heterogeneous nature of LUAD and TC, through APOBEC-mutagenesis and CNA illustrate the challenges facing treatment outcomes.

EGFR gene copy number alterations are not a useful screening tool for predicting EGFR mutation status in lung adenocarcinoma

Pathology ◽  
2014 ◽  
Vol 46 (1) ◽  
pp. 32-36
Author(s):  
Prudence A. Russell ◽  
Y.U. Yong ◽  
D.O. Hongdo ◽  
Timothy D. Clay ◽  
Melissa M. Moore ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Screening Tool ◽  
Egfr Mutation ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
Mutation Status ◽  
Egfr Gene

Targeted Oligonucleotide Array Assessment of Genomic Copy Number Alterations for Risk Stratification in Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1773-1773
Author(s):  
Jane Houldsworth ◽  
Asha Guttapalli ◽  
Xiao J. Yan ◽  
Charles Ma ◽  
Weiyi Chen ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Copy Number ◽  
Array Cgh ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Copy Number Alterations ◽  
Mutation Status ◽  
Copy Number Changes ◽  
Gain Loss ◽  
Genomic Regions

Abstract Abstract 1773 Risk stratification in chronic lymphocytic leukemia (CLL) is highly desirable and should comprise not only evaluation of clinical features but also molecular prognostic markers. Currently such molecular markers include loss of 17p13, 11q22, 13q14, 6q22, and gain of chromosome 12 as assessed by fluorescence in situ hybridization (FISH) and mutation status of the variable region of the IGH gene (IGHV) by sequencing. In recent years, genome-wide scanning technologies such as array-comparative genomic hybridization (array-CGH) have revealed novel and refined known copy number alterations (CNAs) in the CLL genome. In order to evaluate the potential of array-CGH in prognostication in mature B-cell neoplasms, including CLL, and implement array-CGH in a clinical diagnostic laboratory, a targeted oligonucleotide-based microarray was custom designed to represent genomic regions exhibiting gain/loss in these lymphoid neoplasms. The 4 × 44K formatted array included 2 × 17,348 probes for the 80 selected genomic regions (average resolution of 34kbp), and recommended controls including a 1Mbp genome backbone. DNA extracted from two CLL datasets were submitted to array-CGH using an equimixture of commercially available male/female DNA as a reference. CNAs were detected using Genomics Workbench Lite (Agilent Technologies, Inc.) with the ADM2 algorithm. Analytical sensitivity was assessed by cell line DNA dilution and by FISH (116 specimens) and was 30–40% and 20–25%, respectively. Recurrent CNAs in previously untreated patients, greater than 1.5Mbp in size, were analyzed for association with time to first treatment (TTFT) and overall survival (OS) by the log rank test. Association with IGHV mutation status was tested using the Fisher's two-sided exact test. In both datasets for untreated specimens, unmutated IGHV negatively correlated with both TTFT and OS significantly (p < 0.05). Gain of chromosome 12 was detected in 11–12% of untreated specimens in both datasets and as expected did not associate with outcome. Loss of 13q14 as a sole abnormality (excluding copy number changes arising at known sites of normal variation) was associated with an overall favorable outcome, but specimens with loss of both loci (MIR15A/16-1 and RB1) versus one locus (MIR15A/16-1) did not display significantly different outcomes. As expected loss of 17p13 associated with shorter TTFT and OS, and was observed at higher levels in treated specimens. A similar result was observed for 11q22 loss but not in the second dataset, perhaps due to the relatively short follow-up time. Importantly, four additional copy number changes (gain of 2p, 3q, and 8q, and loss of 8p) were found to associate with shorter TTFT and/or OS, and also occurred at higher frequency in treated specimens. Notably, all but one specimen exhibiting two of these CNAs, were Rai Stage 0-II. After multiple comparisons correction, gain of 2p and 3q, and loss of 8p remained significantly associated with an unfavorable outcome. Gain of 2p25.3-p15 was observed exclusively in unmutated IGHV specimens. Loss of 18p and gain of 17q24 were not considered further for testing due to low frequency or lower frequency in treated specimens (data not shown). Uniquely, these data demonstrate in low-intermediate risk CLL cohorts the prognostic value of genomic gain/loss at multiple sites and support implementation of array-CGH into a clinical setting for risk stratification in CLL where genomic gain or loss of multiple clinically relevant genomic regions can be assessed simultaneously. Dataset 1 Untreated n = 81 TTFT p-value OS p-value Treated n = 38 Dataset 2 n = 169 TTFT p-value OS p-value Treated n = 28 Median TTFT 87.6 mo 24.1 mo Median OS 117.7 mo 37.2 mo Rai Stage     0 25 77     I-II 42 48     III-IV 5 1     na 9 43 Unmutated IGHV 46% (n=80) 0.0003 0.0004 38% (n=163) 0.002 0.044 13q14 loss (sole abnormality) 52.5% 0.038‡ 0.087‡ 33.7% 0.144‡ 0.008‡ MIR15A/16-1, RB1 27.5% 0.77 0.337 11.2% 0.011 1 MIR15A/16-1 25.0% 22.5% 11q22 loss (ATM) 12.3% 0.125 0.009 23.7% 8.3% 0.393 0.977 14.3% 17p13 loss (TP53) 2.5% 0.010 0.012 15.8% 4.7% 0.006 <.0001 10.7% 2p25.3-p15 gain 6.2% 0.002 <.0001 10.5% 3.0% 0.702 0.025 10.7% 8q24 gain 2.5% 0.238 0.014 7.9% 4.1% 0.564 0.007 0.0% 3q26-q27 gain 2.5% <.0001 <.0001 5.3% 3.0% 0.850 <.0001 7.1% 8p23-p21 loss 2.5% 0.002 0.016 10.5% 1.2% 1 <.0001 7.1% Unless otherwise noted, all values associated with shorter times ‡ Associated with longer time na not available Disclosures: Houldsworth: Cancer Genetics, Inc.: Employment. Guttapalli:Cancer Genetics, Inc.: Employment. Ma:Cancer Genetics, Inc.: Employment. Chen:Cancer Genetics, Inc.: Employment. Patil:Cancer Genetics, Inc.: Consultancy.

Use of DNA copy number analysis of grade 2-4 gliomas to reveal differences in molecular ontogeny associated with IDH mutation status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2026-2026
Author(s):  
Mariko Sato ◽  
Kenneth D. Aldape ◽  
Clinton C Mason ◽  
Kristin Diefes ◽  
Lindsey Heathcock ◽  
...  
Keyword(s):  
Copy Number ◽  
Genetic Alterations ◽  
Idh1 Mutation ◽  
Low Grade ◽  
Copy Number Alterations ◽  
Copy Number Analysis ◽  
Mutation Status ◽  
Younger Age ◽  
Ffpe Samples ◽  
Molecular Inversion Probes

2026 Background: The genetic alterations of glioma have been studied extensively. IDH1 mutation is associated with younger age and better survival. However, differences in molecular ontogeny within glioma related to IDH1 mutation remain unknown. Here we describe a detailed analysis of copy number alterations (CNA) between IDH1mut vs IDH1wt gliomas of grade 2-3 and 4. Methods: CNA were detected by molecular inversion probes (Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). DNA was extracted from 94 patient FFPE samples including grade 2-3: IDH1wt (n = 17) and IDH1mut (n = 28), and grade IV: IDH1wt ( n = 25) and IDH1mut(n = 24). Chromothripsis was detected using a stringent criteria of at least ten switches of CNA in individual chromosomes. Results: We validated prior findings that IDH1wt GBM have higher frequency of Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN). Other CNA across all grades were: gain of 19q12 and loss of 14q11 in IDH1wt, and gain of 11q21, 10p11, 8q21 and loss of 11p15, 19q13 in IDH1mut. Within grade 2-3 samples, few CNA were associated with mutation status: 2-3wt demonstrated higher frequencies of gain of 7q and loss of 10q, 14q11, and 22q13, while 2-3mut demonstrated higher frequencies of 11q21 gain and 19q13 loss. Grade 4 tumors demonstrated more CNA that differed by mutation status, with 4wt tumors demonstrating gain of 7 and loss of 10 and 14q11, while 4mut demonstrated gains of 8q, 10p, 12p13, 1q23, and loss of 11p15, 3p, 19q13, among others. Comparison of grade 2-3mut vs grade 4mut tumors demonstrated larger number of CNA in the grade 4mut tumors including gain of 1p, 14q, 13q33, 9p, 8q and loss of 22q, 11p15, 10q, and 3p, among others. A significantly higher incidence of chromothripsis events was observed in grade 4mut compared to grade 4wt (p = 0.0374). Conclusions: CNA analysis showed significant differences in molecular ontogeny between IDH1wt and IDH1mut, some of which may further elucidate pathogenesis. Significant CNA increases and increased chromthripsis in grade 4mut support malignant transformation of low grade gliomas through accumulation of genomic instability and genomic catastrophe.

Epidermal Growth Factor Receptor Copy Number Alterations Correlate With Poor Clinical Outcome in Patients With Head and Neck Squamous Cancer

2007 ◽  
Vol 25 (16) ◽  
pp. 2164-2170 ◽  
Author(s):  
Stephane Temam ◽  
Hidetoshi Kawaguchi ◽  
Adel K. El-Naggar ◽  
Jaroslav Jelinek ◽  
Hongli Tang ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Copy Number ◽  
Growth Factor Receptor ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
Egfr Gene ◽  
Copy Numbers ◽  
Epidermal Growth ◽  
Gene Copy Numbers

Purpose Overexpression of epidermal growth factor receptor (EGFR) is common in head and neck squamous cell carcinoma (HNSCC). Recent studies showed that EGFR inhibitors are effective for patients with HNSCC. This study analyzed the genetic nature of EGFR gene in HNSCC and its clinical correlations. Patients and Methods The EGFR gene copy numbers in 134 HNSCC tumors were determined using quantitative real-time polymerase chain reaction. The status of EGFR gene copy numbers was analyzed with clinical parameters including clinical outcome. Mutation status of EGFR exons 18, 19, and 21 was determined in the HNSCC tumors. Results Aberrant EGFR copy numbers were found in 32 (24%) of 134 tumors, including 22 (17%) with increased copy number and 10 (7%) with decreased copy number. Patients whose tumors had EGFR copy number alterations (particularly patients with increased copy numbers) had significantly poorer overall, cancer-specific, and disease-free survivals compared with patients with normal copy numbers (P < .0001). At 5 years after initial diagnosis, 20 (91%) of the 22 patients with increased copy numbers died of disease compared with 30 (29%) of the 102 patients with normal copy number. No mutations on EGFR exons 18, 19, and 21 were detected in any of the tumors. Conclusion A subset of HNSCC manifests EGFR copy number alterations, and this is associated with a poor clinical outcome, suggesting a biologic role of the alterations. The rare mutation or small deletion at EGFR exons 18 to 21 indicates a minimal role of these events in HNSCC.

Sex-dependent differences in DNA copy number alterations in hepatocellular carcinoma

2012 ◽  
Vol 32 (1) ◽  
pp. 5-9 ◽  
Author(s):  
Bing-ji WEN ◽  
Wen-ming CONG ◽  
Ai-zhong WANG ◽  
Song-qin HE ◽  
Hong-mei JIANG ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Dna Copy Number Alterations

scholarly journals EPCO-29. EPIGENOMICS OF THE GLIOMA LONGITUDINAL ANALYSIS (GLASS) CONSORTIUM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii75-ii75
Author(s):  
Thais Sabedot ◽  
Michael Wells ◽  
Indrani Datta ◽  
Tathiane Malta ◽  
Ana Valeria Castro ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Longitudinal Analysis ◽  
Copy Number ◽  
Large Scale ◽  
Molecular Classification ◽  
Tumor Burden ◽  
Copy Number Alterations ◽  
Unsupervised Analysis ◽  
Diffuse Gliomas ◽  
New Biomarkers

Abstract Adult diffuse gliomas are central nervous system (CNS) tumors that arise from the malignant transformation of glial cells. Nearly all gliomas will recur despite standard treatment however, current histopathological grading fails to predict which of them will relapse and/or progress. The Glioma Longitudinal AnalySiS (GLASS) consortium is a large-scale collaboration that aims to investigate the molecular profiling of matched primary and recurrent glioma samples from multiple institutions in order to better understand the dynamic evolution of these tumors. At this time, the cohort comprises 946 samples across 11 institutions and among those, 864 have DNA methylation data available. The current molecular classification based on 7 subtypes published by TCGA in 2016 was applied to the dataset. Among the IDH wildtype tumors, 33% (16/49) of the patients showed a change of subtype upon recurrence, whereas most of them (9/16) were Classic-like at the primary stage but changed to either Mesenchymal-like or PA-like at the recurrent level. Among the IDH mutant tumors, 15% (22/142) showed a change of subtype at recurrent stage, in which 16 out of 22 progressed from G-CIMP-high to G-CIMP-low. Although some tumors progressed to a different subtype upon recurrence, an unsupervised analysis showed that the samples tend to cluster by patient instead of by subtype. By estimating the copy number alterations of these tumors using DNA methylation, the overall copy number profile of the recurrent samples remains similar to their primary counterpart. From this initial analysis using epigenomic data, we were able to characterize some aspects of glioma evolution and how the DNA methylation is associated with the progression of these tumors to different subtypes. These findings corroborate the importance of epigenetics in gliomas and can potentially lead to the identification of new biomarkers that can reflect tumor burden and predict its development.

scholarly journals Cell-free DNA copy number variations predict efficacy of immune checkpoint inhibitor-based therapy in hepatobiliary cancers

2021 ◽  
Vol 9 (5) ◽  
pp. e001942
Author(s):  
Xu Yang ◽  
Ying Hu ◽  
Keyan Yang ◽  
Dongxu Wang ◽  
Jianzhen Lin ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clinical Outcome ◽  
Risk Score ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Copy Number Variations ◽  
Risk Scores ◽  
Free Dna

BackgroundThis study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers.MethodsThree cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel.ResultsBased on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05).ConclusionsThe CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.

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