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21

Whole-Genome Profiling in Liposarcomas Reveals Genetic Alterations Common to Specific Telomere Maintenance Mechanisms


ABSTRACT: Telomere attrition ultimately leads to the activation of protective cellular responses such as apoptosis or senescence. Impairment of such mechanisms can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. Here, we employ a liposarcoma model system to assay telomere maintenance mechanism-specific genetic alterations. A multiassay approach was used to assess the telomere maintenance mechanism(s) active in tumors. Genomic DNA from these samples was then analyzed by high resolution DNA mapping array in order to identify genetic alterations. Our data reveal a higher level of genome instability in ALT-positive tumors as compared with telomerase-positive tumors, whereas tumors lacking both mechanisms have relatively low levels of genome instability. The bulk of the genetic changes are amplifications, regardless of the mode of telomere maintenance employed. We also identified genetic changes specific to the ALT mechanism, e.g., deletion of chromosome 1q32.2-q44, as well as changes that are underrepresented amongst ALT-positive tumors, such as amplification of chromosome 12q14.3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention. Keywords: genotype, genome instability, copy number alteration, liposarcoma, ALT, telomerase, telomere Overall design: Goal: To study telomere maintenance and genetic alterations in liposarcoma using Affymetrix Mapping 50K Xba 240 GeneChip. Brief description: Telomere attrition ultimately leads to the activation of protective cellular responses such as apoptosis or senescence. Impairment of such mechanisms, however, can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. The high-density SNP-based microarrays (e.g., Affymetrix 100K arrays) can detect deletions, amplifications, and loss-of-heterozygosity on a genome in the liposarcoma samples. Chromosomal alterations of liposarcoma should provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention. Quality control steps taken: a. PCR-based quality assessment of liposarcoma tissue genomic DNA b. Nanodrop analysis of preprocessed DNA prior to array hybridization c. Analysis of array call rates following hybridization (array experiments giving call rates of less than 80% were routinely repeated) Data extraction and processing protocols a. Image scanning hardware and software, and processing procedures and parameters: SNP array hybridization was detected using a GCS3000 scanner (Affymetrix). SNP calls and signal quantification were obtained with Gene Chip Operating System (GCOS) 1.2 and Affymetrix GDAS 3.0 with Dynamic Model Mapping Analysis by default settings (0.25) for both homozygote and heterozygote call thresholds. Copy number analyses were carried out using Affymetrix Chromosome Copy Number Analysis Tool (CNAT) 2.1 with a default genomic smoothing window setting of 0.5 Mb. b. Normalization, transformation and data selection procedures and parameters. Array data was normalized by a reference data set with CNAT. c. Definition of chromosomal aberration, amplification, deletion and LOH used for data interpretation: These definitions and their algorithms were described in detail by Huang, et al: Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum Genomics. 2004 May;1(4):287-99.

INSTRUMENT(S): [Mapping50K_Xba240] Affymetrix Human Mapping 50K Xba240 SNP Array

ORGANISM(S): Homo sapiens  

SUBMITTER: Jay Johnson  

PROVIDER: GSE8046 | GEO | 2008-05-01

SECONDARY ACCESSION(S): PRJNA100869

REPOSITORIES: GEO

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