Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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High-resolution genetic analysis of cancer cell lines with near normal karyotypes

ABSTRACT: Cancer development is associated with multiple genetic alterations and genomic instability either at the chromosomal or base pair level is generally thought to underlie these changes. However, it is still unknown whether genetic instability is absolutely required for tumorigenesis. Here we investigated the genomic instability status of four cytogenetically stable diploid cell lines CAL51, SK-UT-1B, A204 and CH1. We applied high resolution 500K single nucleotide polymorphism (SNP) array analysis and found that all the four cell lines have some sub-microscopic genomic copy number changes. Interestingly, there were many more sub-microscopic chromosome alterations in A204 and CH1 than in CAL51 and SK-UT-1B. Twenty-four-color fluorescence in situ hybridization (FISH) was used to analyse a large number of metaphases from CAL51, SK-UT-1B and CH1 cells. The rate of de novo chromosome rearrangements was significantly higher in CH1 than CAL51 and SK-UT-1B. Although this increased rate did not lead to many clonal cytogenetically apparent chromosome alterations in CH1 cells, it is consistent with a first step towards chromosomal instability. It is more striking that both cell lines CAL51 and SK-UT-1B which have a similar de novo chromosomal change rate to that of normal lymphocytes were microsatellite instability positive by BAT-26 microsatellite analysis. This study further strengths the current concept that genomic instability is associated with tumor development. Keywords: DNA copy number changes DNA from A204, CH1, CAL51 and SK-UT-1B were analyzed by Affymetrix Genechip Mapping 500K Set array. Data were compared with normal samples from HAPMAP database.

ORGANISM(S): Homo sapiens

SUBMITTER: Xueying Mao

PROVIDER: E-GEOD-8649 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Subtle genomic alterations and genomic instability revealed in diploid cancer cell lines.

Mao Xueying X Young Bryan D BD Chaplin Tracy T Shipley Janet J Lu Yong-Jie YJ

Cancer letters 20080414 1

To investigate if genomic instability exists in tumors with cytogenetically normal karyotypes, we analyzed four diploid cancer cell lines A204, CAL51, CH1 and SK-UT-1B. We detected subtle genomic changes in all four cell lines. More of these alterations were found in A204 and CH1 than in the microsatellite unstable lines CAL51 and SK-UT-1B. The number of de novo, non-clonal chromosome rearrangements was also significantly higher in CH1 than CAL51 and SK-UT-1B (p=0.001). This study reveals multip ...[more]

PMID: 18407410

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Project description:A common aim of pharmacogenomic studies that employ genome-wide assays on panels of cancers is the unbiased discovery of genomic alterations that are associated with clinical outcome and drug response. Previous investigations of lapatinib, a selective dual-kinase inhibitor of EGFR and HER2 tyrosine kinases, have demonstrated predictable relationships between the activity of these genes and response. Under the hypothesis that additional genes may play a role in promoting sensitivity, a predictive model for lapatinib sensitivity was constructed from genome-wide DNA copy number data from 24 cancer cell lines. An optimal predictive model, which consists of aberrations at nine distinct genetic loci, includes gains of HER2, EGFR, and loss of CDKN2A. This model, which achieved area under the Receiver Operating Characteristic (ROC) curve of ~0.85 (80% confidence interval: 0.70–0.98; P<0.01), and correctly classified the sensitivity status of 8/10 head and neck cancer cell lines. This study demonstrates that previously described biomarkers of lapatinib sensitivity, including copy number gains of EGFR and HER2, can be discovered as powerful predictors of response using novel genomic assays in an unbiased manner. Further, these results demonstrate the utility of DNA copy number profiles in pharmacogenomic studies. Keywords: Comparative Genomic Hybridization Basal DNA copy number profiles were derived from Affymetrix 'SNP chips' for a panel of 34 tumor derived cell lines. Each of these cell lines were tested for their degree of sensitivity to lapatinib. Specific DNA alterations associating with lapatinib sensitivity were identified using a training set consisting of 24 of these lines. A predictive model was constructed from these loci. The remaining 10 lines were used to test the model performance. A panel of chips (n = 12) assayed with germline DNA served as a reference in order to calculate the test/reference ratios reported in the Sample table VALUE columns. The 'reference' Samples for the 500K and 100K assays are as follows: 500K: GSM188024, GSM188025, GSM188026, GSM188027, GSM188028, GSM188029, GSM188030, GSM188031, GSM188032, GSM188033, GSM188034, GSM188035, GSM188048, GSM188049, GSM188050, GSM188051, GSM188052, GSM188053, GSM188054, GSM188055, GSM188056, GSM188057, GSM188058, GSM188059 100K: GSM187950, GSM187951, GSM187952, GSM187953, GSM187954, GSM187955, GSM187956, GSM187957, GSM187958, GSM187959, GSM187960, GSM187961, GSM187949, GSM187948, GSM187946, GSM187947, GSM187945, GSM187944, GSM187943, GSM187942, GSM187941, GSM187940, GSM187939, GSM187938

Dataset Information

High-resolution genetic analysis of cancer cell lines with near normal karyotypes

Publications

Subtle genomic alterations and genomic instability revealed in diploid cancer cell lines.

Similar Datasets

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