Quantification of Normal Cell Fraction and Copy Number Neutral LOH in Clinical Lung Cancer Samples Using SNP Array Data
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE16092 | GEO | 2009/08/11
SECONDARY ACCESSION(S): PRJNA115457
REPOSITORIES: GEO
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Project description:Technologies based on DNA microarrays have the potential to provide detailed information on genomic aberrations in tumor cells. In practice a major obstacle for quantitative detection of aberrations is the heterogeneity of clinical tumor tissue. Tumor tissue consists of a mixture of tumor cells and normal cells, including inflammatory and stromal cells, which may lead to a failure to detect aberrations in the tumor cells. Principal finding: Using SNP array data from 43 non-small cell lung cancer samples we have developed a bioinformatic algorithm that accurately models the fractions of normal and tumor cells in clinical tumor samples. The proportion of normal cells and SNP array data can be used to detect and quantify copy number neutral loss-of-heterozygosity (CNNLOH) in the tumor cells both in crude tumor tissue and in samples enriched for tumor cells by laser capture microdissection. Conclusion: Genome-wide quantitative analysis of CNNLOH using the CNNLOH Quantifier method can help to identify recurrent aberrations contributing to tumor development in clinical tumor samples. In addition, SNP-array based analysis of CNNLOH may become important for detection of aberrations that can be used for diagnostic and prognostic purposes, as well as to predict response to therapy.
2010-04-09 | E-GEOD-16092 | biostudies-arrayexpress
Project description:BACKGROUND: Technologies based on DNA microarrays have the potential to provide detailed information on genomic aberrations in tumor cells. In practice a major obstacle for quantitative detection of aberrations is the heterogeneity of clinical tumor tissue. Since tumor tissue invariably contains genetically normal stromal cells, this may lead to a failure to detect aberrations in the tumor cells. PRINCIPAL FINDING: Using SNP array data from 44 non-small cell lung cancer samples we have developed a bioinformatic algorithm that accurately models the fractions of normal and tumor cells in clinical tumor samples. The proportion of normal cells in combination with SNP array data can be used to detect and quantify copy number neutral loss-of-heterozygosity (CNNLOH) in the tumor cells both in crude tumor tissue and in samples enriched for tumor cells by laser capture microdissection. CONCLUSION: Genome-wide quantitative analysis of CNNLOH using the CNNLOH Quantifier method can help to identify recurrent aberrations contributing to tumor development in clinical tumor samples. In addition, SNP-array based analysis of CNNLOH may become important for detection of aberrations that can be used for diagnostic and prognostic purposes.
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Project description:Dermal neurofibromas (dNFs) are benign tumors of the peripheral nervous system typically associated with Neurofibromatosis type 1 (NF1) patients. Genes controlling the integrity of the DNA are likely to influence the number of neurofibromas developed because dNFs are caused by somatic mutational inactivation of the NF1 gene, frequently evidenced by loss of heterozygosity (LOH). We performed a comprehensive analysis of the prevalence and mechanisms of LOH in dNFs. Our study included 518 dNFs from 113 patients. LOH was detected in 25% of the dNFs (N = 129). The most frequent mechanism causing LOH was mitotic recombination, which was observed in 62% of LOH-tumors (N = 80), and which does not reduce the number of NF1 gene copies. All events were generated by a single crossover located between the centromere and the NF1 gene, resulting in isodisomy of 17q. LOH due to the loss of the NF1 gene accounted for a 38% of dNFs with LOH (N = 49), with deletions ranging in size from ?80?kb to ?8?Mb within 17q. In one tumor we identified the first example of a neurofibroma-associated second-hit type-2 NF1 deletion. Analysis of the prevalence of mechanisms causing LOH in dNFs in individual patients (possibly under genetic control) will elucidate whether there exist interindividual variation.
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Project description:High-resolution microarray-based whole genome genotyping (WGG) techniques based on SNP analysis have successfully been applied in cancer genomics to study gene copy number alterations and allele-specific aberrations such as loss-of-heterozygosity (LOH). Problems in data interpretation arise when WGG is applied on tumor tissue specimens, in which normal cell components and tumor subpopulations frequently exist. Such heterogeneity may lead to reduced detection of cancer cell specific genomic alterations. To circumvent problems with sample heterogeneity, we propose using a segmentation strategy derived from DNA copy number analysis for detection of LOH and allelic imbalance. We generated an experimental dilution series of a tumor cell line mixed with its paired normal cell line and simulated data for such dilutions to test the strategy. We also used data sets generated on both Affymetrix and Illumina WGG platforms, including paired tumor-normal samples and tumors previously characterized by FISH. We tested the segmentation strategy against several reported algorithms. We demonstrate high sensitivity and specificity of the segmentation strategy for detecting both minute and gross allelic imbalances originating from DNA copy number gain, loss, and neutral events in tumor specimens. For example, hemizygous copy number loss can be detected in samples containing only 20-25% tumor cells. Furthermore, the strategy can identify cell subpopulation specific events and accurately estimate the fraction of cells affected by an allelic imbalance. Thus, the segmentation strategy extends the usefulness of WGG platforms for investigation of allelic imbalances in heterogeneous tumor genomes.
2008-09-18 | GSE11976 | GEO
Project description:Single nucleotide polymorphism (SNP) microarrays are commonly applied to tumors to identify genomic regions with copy number alterations (CNA) or loss of heterozygosity (LOH). However, in typical tumor specimens collected in clinical studies, up to 60% of the DNA derives from stromal cells with a normal genome, resulting in attenuated sensitivity to true somatic aberrations in the tumor. Here we describe SNPfilter, a model-based method to decompose SNP array data from heterogeneous tumor specimens into their corresponding normal and tumor profiles. Unlike existing methods, SNPfilter does not require paired normal control data. We assessed the performance of this method using SNP array data representing cancer cell lines with aberrant genomes, B-cell lymphoblastoid cell lines with normal genomes, and defined mixtures of the two. In the pure tumor samples, SNPfilter identified CNA and LOH regions with accuracy similar to existing methods. In the mixture samples containing 40–80% tumor genomic DNA, SNPfilter yielded prediction sensitivity superior to existing methods. Thus, SNPfilter provides a powerful tool for discovery of clinically relevant somatic aberrations in tumor genomes.
2011-12-30 | GSE34754 | GEO
Project description:High frequency of loss of heterozygosity (LOH) at locus D4S2964 was found in hepatocellular carcinoma (HCC) by our previous studies and others’. The present study was designed to explore genes around the locus affected by LOH and their clinical implications. 440 SNPs located at 49 genes around D4S2964 were selected from NCBI website for the SNPs microarray fabrication. LOH of these SNPs markers in 112 cases of HCC tissues and paired adjacent liver tissues were investigated by the SNP microarray. A map of LOH of SNPs in genes around D4S2964 was constructed. 112 pairs of HCC tissues and corresponding non-tumor tissues was genotyped. LOH and its clinical implication was analyzed.
2015-02-28 | E-GEOD-36277 | biostudies-arrayexpress
Project description:We have employed a laser capture microdissection technique and single nucleotide polymorphism arrays to characterize genomic alterations associated with the development of glioblastomas. Combined analysis of LOH and copy number revealed that more than half of the identified 254 LOH loci showed no copy number alteration, indicating the presence of copy-number neutral LOH Keywords: DNA copy number, Loss of heterozygosity
2009-03-01 | GSE10922 | GEO
Project description:Cytogenetic profiling of morphologically-distinct structures of breast tumors: tubular, alveolar, solid, trabecular structures, and discrete groups of tumor cells. The aim was to identify chromosomal aberrations which could be associated with the development of clinical relevant structures of tumor cells.
2016-04-29 | GSE80758 | GEO
Project description:Background & Aims: The metastatic process is complex and remains a major obstacle in the management of colorectal cancer (CRC). To gain a better insight into the biologic events driving the metastatic process we investigated genomic aberrations in a large cohort of matched CRC primaries and distant metastases from various sites. Methods: In total, 62 primary colorectal cancers, 62 matched normal specimens, and 68 matched metastases (from liver, lung, ovary, omentum, and distant lymph nodes) were analyzed by high resolution array comparative genomic hybridization (array CGH) for DNA copy number changes. Findings were validated using a publicly available dataset consisting of 21 primary tumors and matched liver metastases. Fluorescence in situ hybridization (FISH) was used to confirm some of the DNA copy number changes observed. Results: Overall patterns of DNA copy number aberrations were highly similar between primary tumors and their metastases, confirming clonality. Additional copy number aberrations in metastasis are rare and rather than recurrent they were sporadic for individual patients. The only recurrent differences between primary tumors and their metastases were two chromosomal regions, 6q21 and 8q24.21 encompassing the MYC oncogene, that coamplified in three metastases of two patients (3.2%). FISH analysis confirmed the high level co-amplification in the metastasis, which were not detected in their primary tumors. Conclusions: Primary CRC and their metastases show highly similar patterns of DNA copy number changes, additional copy number aberrations in metastasis are rare and recurrences exceptional. These observations are consistent with the hypothesis that the metastatic potential is predestined early in the development of the primary tumor. In total, 62 primary colorectal cancers, 62 matched normal specimens, and 68 matched metastases (liver, lung, ovarian, omentum and distant lymph nodes) were analyzed by high resolution array comparative genomic hybridization (array CGH).
2014-02-10 | E-GEOD-38479 | biostudies-arrayexpress
Project description:Angiomyolipoma (AML) is classified as a perivascular epithelioid cell neoplasm, mostly occurring in the kidney. Twenty percent of patients with renal AML have tuberous sclerosis complex (TSC) caused by germline variation in the TSC1 or TSC2 gene. In this paper, we report the first case of renal AML harboring somatic missense mutations of the TSC2 gene and concomitant copy-neutral loss of heterozygosity (CN-LOH). The patient presented with solitary renal AML and pulmonary lymphangiomyomatosis and without other findings suggestive of TSC. Exome sequencing analysis of the renal AML, however, identified a pathogenic somatic missense mutation in the TSC2 gene (NM_000548:c.5228G>A:p. R1743Q), although no other somatic mutation was detected. Furthermore, no germline mutation in TSC1 or TSC2 was detected. Interestingly, the mutant allele ratio was too high for a somatic heterozygous mutation without loss of heterozygosity (LOH). Furthermore, no copy number variation was detected around the TSC2 locus (16p13.3). To clarify the allelic status, we analyzed heterozygous single-nucleotide polymorphisms (SNPs) in chromosome 16. In these SNPs, an unbalanced allele ratio was accumulated inside the 16p13.3 region. These results suggested copy-neutral LOH (CN-LOH). Consequently, we concluded that the missense mutation of the TSC2 gene and CN-LOH of the TSC2 locus caused renal AML.
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