GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data

Lyng, Heidi; Lando, Malin; Brøvig, Runar S; Svendsrud, Debbie Hege; Johansen, Morten; Galteland, Eivind; Brustugun, Odd Terje; Meza‐Zepeda, Leonardo A.; Myklebost, Ola; Kristensen, Gunnar B.; Hovig, Eivind; Stokke, Trond

doi:10.1186/gb-2008-9-5-r86

Cited by 14 publications

(26 citation statements)

References 40 publications

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“…In line with Nancarrow and colleagues (34) For accurate estimates of the allelic states of CNAs in FFPE aneuploid tumors, we showed that integration of the DNA index in conjunction with SNP arrays (8,27) is crucial. Otherwise, most, if not all, CNAs will be misinterpreted, which is also supported by the findings of Lyng and coworkers on aCGH (16). For example, the patterns of CNAs on chromosomes 8 and 18 of the near-diploid and the aneuploid fractions of case 5 seem to be identical, but their allelic states are shown to differ after integration of the DNA index (Fig.…”

Section: Discussionsupporting

confidence: 63%

“…These differences also show that intratumor heterogeneity is more extensive than is generally observed by ploidy and LAIR analysis because both techniques register the dominant clone(s). Intratumor heterogeneity has also been identified by aCGH (16). However, LAIR analysis has increased value relative to classical methods.…”

Section: Discussionmentioning

confidence: 99%

“…Yamamoto and colleagues (14) analyzed cell lines and acute leukemia with limited CNAs and a mostly hyperdiploid DNA content (15). A recent study from Lyng and colleagues clearly showed the necessity for measuring the DNA index for calculation of absolute copy numbers from aCGH data (16). Also, varying proportions of normal cells (inflammatory and stromal cells) impair the detection of genomic and genetic alterations in tumor samples.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide Allelic State Analysis on Flow-Sorted Tumor Fractions Provides an Accurate Measure of Chromosomal Aberrations

Corver

Middeldorp²,

Haar³

et al. 2008

Cancer Research

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Chromosomal aberrations are a common characteristic of cancer and are associated with copy number abnormalities and loss of heterozygosity (LOH). Tumor heterogeneity, low tumor cell percentage, and lack of knowledge of the DNA content impair the identification of these alterations especially in aneuploid tumors. To accurately detect allelic changes in carcinomas, we combined flow-sorting and single nucleotide polymorphism arrays. Cells derived from archival cervical and colon cancers were flow-sorted based on differential vimentin and keratin expression and DNA content and analyzed on single nucleotide polymorphism arrays. A new algorithm, the lesser allele intensity ratio, was used to generate a molecular measure of chromosomal aberrations for each case. Flow-sorting significantly improved the detection of copy number abnormalities; 31.8% showed an increase in amplitude and 23.2% were missed in the unsorted fraction, whereas 15.9% were detected but interpreted differently. Fluorescence in situ hybridization copy numbers, as well as the high similarity between the DNA index and the allelic state index, which is the average of the allelic states across the genome, validated the method. This new approach provides an individual molecular measure of chromosomal aberrations and will likely have repercussions for preoperative molecular staging, classification, and prognostic profiling of tumors, particularly for heterogeneous aneuploid tumors, and allows the study of the underlying molecular genetic mechanisms and clonal evolution of tumor subpopulations. [Cancer Res 2008;68(24):10333-40]

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genome-wide Allelic State Analysis on Flow-Sorted Tumor Fractions Provides an Accurate Measure of Chromosomal Aberrations

Corver

Middeldorp²,

Haar³

et al. 2008

Cancer Research

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“…Although some studies aim to bring these effects into the equation (22,23), these difficulties still remain today. In addition to these limitations, array-CGH provides no information regarding which of the two alternative alleles has been gained or lost, and it overlooks copy numberneutral aberrations.…”

Section: −3mentioning

confidence: 99%

Allele-specific copy number analysis of tumors

Loo

Nordgard

Lingjærde

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

1,052

1,133

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We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number analysis of tumors), to accurately dissect the allele-specific copy number of solid tumors, simultaneously estimating and adjusting for both tumor ploidy and nonaberrant cell admixture. This allows calculation of "ASCAT profiles" (genome-wide allele-specific copy-number profiles) from which gains, losses, copy number-neutral events, and loss of heterozygosity (LOH) can accurately be determined. In an early-stage breast carcinoma series, we observe aneuploidy (>2.7n) in 45% of the cases and an average nonaberrant cell admixture of 49%. By aggregation of ASCAT profiles across our series, we obtain genomic frequency distributions of gains and losses, as well as genome-wide views of LOH and copy number-neutral events in breast cancer. In addition, the ASCAT profiles reveal differences in aberrant tumor cell fraction, ploidy, gains, losses, LOH, and copy number-neutral events between the five previously identified molecular breast cancer subtypes. Basal-like breast carcinomas have a significantly higher frequency of LOH compared with other subtypes, and their ASCAT profiles show large-scale loss of genomic material during tumor development, followed by a whole-genome duplication, resulting in neartriploid genomes. Finally, from the ASCAT profiles, we construct a genome-wide map of allelic skewness in breast cancer, indicating loci where one allele is preferentially lost, whereas the other allele is preferentially gained. We hypothesize that these alternative alleles have a different influence on breast carcinoma development.breast carcinoma | single-nucleotide polymorphism arrays | bioinformatics | cancer

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“…Absolute DNA copy numbers were calculated from the aCGH ratios by the GeneCount algorithm, and were corrected for tumor ploidy, as determined by flow cytometry, and normal cell fraction of the samples35 . Samples showing two distinct G 1 peaks in the DNA histogram by flow cytometry were classified as aneuploid, and the ploidy was determined from the position of the G 1 peak of the aneuploid cells relative to the corresponding peak of the diploid cells.…”

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confidence: 99%

Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer

et al. 2015

Self Cite

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Loss of 3p11-p14 is a frequent event in epithelial cancer and a candidate prognostic biomarker in cervical cancer. In addition to loss, promoter methylation can participate in gene silencing and promote tumor aggressiveness. We have performed a complete mapping of promoter methylation at 3p11-p14 in two independent cohorts of cervical cancer patients (n = 149, n = 121), using Illumina 450K methylation arrays. The aim was to investigate whether hyperm-ethylation was frequent and could contribute to gene silencing and disease aggressiveness either alone or combined with loss. By comparing the methylation level of individual CpG sites with corresponding data of normal cervical tissue, 26 out of 41 genes were found to be hypermethylated in both cohorts. The frequency of patients with hypermethylation of these genes was found to be higher at tumor stages of 3 and 4 than in stage 1 tumors. Seventeen of the 26 genes were transcriptionally downregulated in cancer compared to normal tissue, whereof 6 genes showed a significant correlation between methylation and expression. Integrated analysis of methylation, gene dosage, and expression of the 26 hypermethylated genes identified 3 regulation patterns encompassing 8 hypermethylated genes; a methylation driven pattern (C3orf14, GPR27, ZNF717), a gene dosage driven pattern (THOC7, PSMD6), and a combined methylation and gene dosage driven pattern (FHIT, ADAMTS9, LRIG1). In survival analysis, patients with both hypermethylation and loss of LRIG1 had a worse outcome compared to those harboring only hypermethylation or none of the events. C3orf14 emerged as a novel methylation regulated suppressor gene, for which knockdown was found to promote invasive growth in human papilloma virus (HPV)-transformed keratinocytes. In conclusion, hypermethylation at 3p11-p14 is common in cervical cancer and may exert a selection pressure during carcinogenesis alone or combined with loss. Information on both events could lead to improved prognostic markers.

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GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data

Cited by 14 publications

References 40 publications

Genome-wide Allelic State Analysis on Flow-Sorted Tumor Fractions Provides an Accurate Measure of Chromosomal Aberrations

Genome-wide Allelic State Analysis on Flow-Sorted Tumor Fractions Provides an Accurate Measure of Chromosomal Aberrations

Allele-specific copy number analysis of tumors

Interplay between promoter methylation and chromosomal loss in gene silencing at 3p11-p14 in cervical cancer

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