scholarly journals GeneBreak: detection of recurrent DNA copy number aberration-associated chromosomal breakpoints within genes

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 2340
Author(s):  
Evert van den Broek ◽  
Stef van Lieshout ◽  
Christian Rausch ◽  
Bauke Ylstra ◽  
Mark A. van de Wiel ◽  
...  
Keyword(s):  
Computational Methods ◽  
Chromosomal Aberrations ◽  
Copy Number ◽  
Comparative Genomic ◽  
Multiple Testing Correction ◽  
Dna Copy Number ◽  
Link Type ◽  
Genomic Location ◽  
A Genome ◽  
Chromosomal Breakpoints

Development of cancer is driven by somatic alterations, including numerical and structural chromosomal aberrations. Currently, several computational methods are available and are widely applied to detect numerical copy number aberrations (CNAs) of chromosomal segments in tumor genomes. However, there is lack of computational methods that systematically detect structural chromosomal aberrations by virtue of the genomic location of CNA-associated chromosomal breaks and identify genes that appear non-randomly affected by chromosomal breakpoints across (large) series of tumor samples. ‘GeneBreak’ is developed to systematically identify genes recurrently affected by the genomic location of chromosomal CNA-associated breaks by a genome-wide approach, which can be applied to DNA copy number data obtained by array-Comparative Genomic Hybridization (CGH) or by (low-pass) whole genome sequencing (WGS). First, ‘GeneBreak’ collects the genomic locations of chromosomal CNA-associated breaks that were previously pinpointed by the segmentation algorithm that was applied to obtain CNA profiles. Next, a tailored annotation approach for breakpoint-to-gene mapping is implemented. Finally, dedicated cohort-based statistics is incorporated with correction for covariates that influence the probability to be a breakpoint gene. In addition, multiple testing correction is integrated to reveal recurrent breakpoint events. This easy-to-use algorithm, ‘GeneBreak’, is implemented in R (www.cran.r-project.org) and is available from Bioconductor (www.bioconductor.org/packages/release/bioc/html/GeneBreak.html).

scholarly journals GeneBreak: detection of recurrent DNA copy number aberration-associated chromosomal breakpoints within genes

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2340 ◽  
Author(s):  
Evert van den Broek ◽  
Stef van Lieshout ◽  
Christian Rausch ◽  
Bauke Ylstra ◽  
Mark A. van de Wiel ◽  
...  
Keyword(s):  
Computational Methods ◽  
Chromosomal Aberrations ◽  
Copy Number ◽  
Comparative Genomic ◽  
Multiple Testing Correction ◽  
Dna Copy Number ◽  
Link Type ◽  
Genomic Location ◽  
A Genome ◽  
Chromosomal Breakpoints

Development of cancer is driven by somatic alterations, including numerical and structural chromosomal aberrations. Currently, several computational methods are available and are widely applied to detect numerical copy number aberrations (CNAs) of chromosomal segments in tumor genomes. However, there is lack of computational methods that systematically detect structural chromosomal aberrations by virtue of the genomic location of CNA-associated chromosomal breaks and identify genes that appear non-randomly affected by chromosomal breakpoints across (large) series of tumor samples. ‘GeneBreak’ is developed to systematically identify genes recurrently affected by the genomic location of chromosomal CNA-associated breaks by a genome-wide approach, which can be applied to DNA copy number data obtained by array-Comparative Genomic Hybridization (CGH) or by (low-pass) whole genome sequencing (WGS). First, ‘GeneBreak’ collects the genomic locations of chromosomal CNA-associated breaks that were previously pinpointed by the segmentation algorithm that was applied to obtain CNA profiles. Next, a tailored annotation approach for breakpoint-to-gene mapping is implemented. Finally, dedicated cohort-based statistics is incorporated with correction for covariates that influence the probability to be a breakpoint gene. In addition, multiple testing correction is integrated to reveal recurrent breakpoint events. This easy-to-use algorithm, ‘GeneBreak’, is implemented in R (www.cran.r-project.org) and is available from Bioconductor (www.bioconductor.org/packages/release/bioc/html/GeneBreak.html).

scholarly journals Deletion of Chromosome 4q Predicts Outcome in Stage II Colon Cancer Patients

2010 ◽  
Vol 33 (2) ◽  
pp. 95-104 ◽  
Author(s):  
R. P. M. Brosens ◽  
E. J. T. H. Belt ◽  
J. C. Haan ◽  
T. E. Buffart ◽  
B. Carvalho ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Cancer Patients ◽  
Copy Number ◽  
Multiple Testing ◽  
Stage Ii ◽  
Comparative Genomic ◽  
Multiple Testing Correction ◽  
Dna Copy Number ◽  
Stage Ii Colon Cancer

Background: Around 30% of all stage II colon cancer patients will relapse and die of their disease. At present no objective parameters to identify high-risk stage II colon cancer patients, who will benefit from adjuvant chemotherapy, have been established. With traditional histopathological features definition of high-risk stage II colon cancer patients is inaccurate. Therefore more objective and robust markers for prediction of relapse are needed. DNA copy number aberrations have proven to be robust prognostic markers, but have not yet been investigated for this specific group of patients. The aim of the present study was to identify chromosomal aberrations that can predict relapse of tumor in patients with stage II colon cancer.Materials and Methods: DNA was isolated from 40 formaldehyde fixed paraffin embedded stage II colon cancer samples with extensive clinicopathological data. Samples were hybridized using Comparative Genomic Hybridization (CGH) arrays to determine DNA copy number changes and microsatellite stability was determined by PCR. To analyze differences between stage II colon cancer patients with and without relapse of tumor a Wilcoxon rank-sum test was implemented with multiple testing correction.Results: Stage II colon cancers of patients who had relapse of disease showed significantly more losses on chromosomes 4, 5, 15q, 17q and 18q. In the microsatellite stable (MSS) subgroup (n=28), only loss of chromosome 4q22.1–4q35.2 was significantly associated with disease relapse (p < 0.05, FDR < 0.15). No differences in clinicopathological characteristics between patients with and without relapse were observed.Conclusion: In the present series of MSS stage II colon cancer patients losses on 4q22.1–4q35.2 were associated with worse outcome and these genomic alterations may aid in selecting patients for adjuvant therapy.

scholarly journals Mixed Gastric Carcinomas Show Similar Chromosomal Aberrations in Both their Diffuse and Glandular Components

2006 ◽  
Vol 28 (5-6) ◽  
pp. 283-294
Author(s):  
Beatriz Carvalho ◽  
Tineke E. Buffart ◽  
Rui M. Reis ◽  
Thomas Mons ◽  
Cátia Moutinho ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Chromosomal Aberrations ◽  
Copy Number ◽  
Array Cgh ◽  
Comparative Genomic Hybridisation ◽  
Comparative Genomic ◽  
Dna Copy Number ◽  
Gastric Carcinomas ◽  
Phenotypic Divergence ◽  
Copy Number Changes

Gastric cancer is one of the most frequent malignancies in the world. Nonetheless, the knowledge of the molecular events involved in the development of gastric carcinoma is far from complete. One of the hallmarks of gastric cancer is chromosomal instability resulting in abnormal DNA copy number changes throughout the genome. Mixed gastric carcinomas constitute a rare histological entity, containing the two main histological phenotypes (diffuse and intestinal). Very little is known about the underlying mechanisms of phenotypic divergence in these mixed tumours. To the best of our knowledge only E-Cadherin mutations were implicated so far in the divergence of these tumours and nothing is known about the involvement of chromosome copy number changes in the two divergent histological components. In this study, we compared the DNA copy number changes, in the two different components (diffuse and intestinal) of mixed gastric carcinomas by microarray – comparative genomic hybridisation (array CGH). The analysis of 12 mixed gastric carcinomas showed no significant differences in array CGH profiles between the diffuse and intestinal components of mixed carcinomas. This supports the idea that the phenotypic divergence within mixed gastric carcinomas is not caused by DNA chromosomal aberrations.

Genomic DNA Copy Number Alterations Present in AML Bone Marrow Samples with Normal Cytogenetics.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 142-142 ◽  
Author(s):  
Matthew J. Walter ◽  
Rhonda E. Ries ◽  
Jon Armstrong ◽  
Brian O’Gara ◽  
James W. Vardiman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Copy Number ◽  
Genomic Dna ◽  
Array Cgh ◽  
Comparative Genomic ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Prognostic Information ◽  
Normal Cytogenetics ◽  
Copy Number Changes

Abstract Cytogenetics and comparative genomic hybridization (CGH) have been used to identify large genomic amplifications and deletions in all subtypes of acute myeloid leukemia (AML). Up to 15–20% of AML patients have a normal karyotype at diagnosis. While cytogenetic abnormalities confer important prognostic information for patients with AML, there remain differences in the therapeutic response and outcome among patients with the same cytogenetic profile, implying that other, more subtle, genetic abnormalities may exist. We hypothesized that a subset of AML patients with normal cytogenetics may contain genomic DNA copy number changes that are too small to be detected using standard cytogenetic techniques. To address this possibility, we used high-resolution bacterial artificial chromosome (BAC) array CGH technology to examine 31 AML patients with normal cytogenetics. The BAC arrays contain 2,464 BAC clones spotted in triplicate on glass slides, and provide a 1 Mb resolution of the entire human genome. Technical generation of the arrays, hybridization parameters, and analysis were similar to that reported for murine BAC array CGH (Nat Genet. 2001 Dec;29(4):459–64). The 31 AML samples included 4 M0, 8 M1, 10 M2, and 9 M4 patients. Array CGH experiments were performed using 500 nanograms of Cyanine 5 labeled genomic DNA from unmanipulated AML bone marrow, mixed with an equal amount of control DNA (a pool of DNA from 4 cancer-free individuals) labeled with Cyanine 3. Using the human 1 Mb BAC arrays, we identified amplifications and deletions from multiple samples that were confirmed with G-banding cytogenetics [del(7)(q31), del(7)(p11.2), +8, del(11)(q13q23), +21, add(21)(q22), −X, −Y, +Y]. In addition, BAC arrays robustly detected copy number alterations that were identified in as few as 4/21 metaphases. We identified 5/31 (16%) patients with normal cytogenetics that contained altered genomic DNA copy numbers using BAC array CGH. Copy number changes were confirmed for several of these genomic loci using a dye-swap experiment, where the AML DNA was labeled with Cyanine 3, and the control DNA with Cyanine 5. Two of the 5 patients with abnormalities detected using array CGH would be reclassified from “intermediate” to “unfavorable” cytogenetics [del(7)(q31.31q34), add(11)(q23.3qter), and 17(p12pter)]. These results suggest that a subset of AML patients with normal cytogenetics contain genomic copy number alterations that may effect treatment and outcome. Patient # FAB subtype Genomic location Gain or loss Size (Megabase) Dye-Swap confirmed 1 M0 7(q31.31q34) loss 2.0 Not done 1 11(q23.3qter) gain 16.5 Not done 2 M1 11(p14) loss 7.4 Yes 3 M1 11(q13.2q14.1) gain 15.8 Yes 3 19(p) gain 64.0 Yes 4 M2 17(p12pter) gain 8.6 Not Done 5 M2 19(p13.1pter) loss 14.8 Yes 5 12(q13) loss 5.0 Yes

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