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Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma (Illumina)

ABSTRACT: Inflammatory leiomyosarcoma (ILMS) is a soft tissue tumor that morphologically resembles conventional leiomyosarcoma (LMS) admixed with a prominent inflammatory infiltrate. Genetic data on ILMS are still limited but have suggested that this entity is characterized by hyperhaploidy (24-34 chromosomes). This low chromosome number is otherwise uncommon in neoplasia and has been found only in 0.2-0.3% of cytogenetically investigated tumors. Here, three ILMS were investigated using cytogenetic, SNP array and global gene expression analyses. All cases displayed a hyperhaploid origin. Combined with previously reported cases, hyperhaploidy has been found in six of seven cytogenetically investigated ILMS. The copy number distribution of individual chromosomes is clearly nonrandom; the hyperhaploid clones of all six cases displayed disomy for chromosomes 5 and 20, and two copies of chromosomes 18, 21 and 22 were also common. All chromosomes identified as disomic showed a biparental origin by SNP array analysis; whether this is of pathogenetic importance is not known. Compared with conventional LMS, ILMS had a distinct gene expression signature. Furthermore, the number of chromosome copies correlated well with gene expression levels, a finding which has not previously been reported for hyperhaploid tumors. Genes on disomic chromosomes showed higher expression levels in ILMS compared to LMS and disomic chromosomes showed higher average gene expression levels than monosomic chromosomes. Taken together, our findings suggest that disomy for some chromosomes, notably 5 and 20, as well as distorted gene expression balance achieved through massive loss of other chromosomes are essential for the development of ILMS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE38015 | GEO | 2013/05/22

SECONDARY ACCESSION(S): PRJNA167213

REPOSITORIES: GEO

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Project description:Inflammatory leiomyosarcoma (ILMS) is a soft tissue tumor that morphologically resembles conventional leiomyosarcoma (LMS) admixed with a prominent inflammatory infiltrate. Genetic data on ILMS are still limited but have suggested that this entity is characterized by hyperhaploidy (24-34 chromosomes). This low chromosome number is otherwise uncommon in neoplasia and has been found only in 0.2-0.3% of cytogenetically investigated tumors. Here, three ILMS were investigated using cytogenetic, SNP array and global gene expression analyses. All cases displayed a hyperhaploid origin. Combined with previously reported cases, hyperhaploidy has been found in six of seven cytogenetically investigated ILMS. The copy number distribution of individual chromosomes is clearly nonrandom; the hyperhaploid clones of all six cases displayed disomy for chromosomes 5 and 20, and two copies of chromosomes 18, 21 and 22 were also common. All chromosomes identified as disomic showed a biparental origin by SNP array analysis; whether this is of pathogenetic importance is not known. Compared with conventional LMS, ILMS had a distinct gene expression signature. Furthermore, the number of chromosome copies correlated well with gene expression levels, a finding which has not previously been reported for hyperhaploid tumors. Genes on disomic chromosomes showed higher expression levels in ILMS compared to LMS and disomic chromosomes showed higher average gene expression levels than monosomic chromosomes. Taken together, our findings suggest that disomy for some chromosomes, notably 5 and 20, as well as distorted gene expression balance achieved through massive loss of other chromosomes are essential for the development of ILMS. Tumor DNA was hybridized onto Illumina Human CNV370-Quad v3_C (case 1) and Illumina Human CNV370 v1_C (cases 2 and 3) BeadChips, containing ~370,000 markers, following standard protocols supplied by the manufacturer (Illumina). Data analysis was performed using the GenomeStudio software (Illumina), detecting imbalances by visual inspection.

Project description:Near-haploid chromosome numbers have been found in less than 1% of cytogenetically reported tumors, but seem to be more common in certain neoplasms including the malignant cartilage-producing tumor chondrosarcoma. By a literature survey of published karyotypes from chondrosarcomas we could confirm that loss of chromosomes resulting in hyperhaploid-hypodiploid cells is common and that these cells may polyploidize. Sixteen chondrosarcomas were investigated by single nucleotide polymorphism (SNP) array and the majority displayed SNP patterns indicative of a hyperhaploid-hypodiploid origin, with or without subsequent polyploidization. Except for chromosomes 5, 7, 19, 20 and 21, autosomal loss of heterozygosity was commonly found, resulting from chromosome loss and subsequent duplication of monosomic chromosomes giving rise to uniparental disomy. Additional gains, losses and rearrangements of genetic material, and even repeated rounds of polyploidization, may affect chondrosarcoma cells resulting in highly complex karyotypes. Loss of chromosomes and subsequent polyploidization was not restricted to a particular chondrosarcoma subtype and, although commonly found in chondrosarcoma, binucleated cells did not seem to be involved in these events. Tumor DNA was hybridized onto Illumina Human Omni-Quad v1.0 BeadChip or Human CNV370-Quad v3.0 BeadChip (Illumina, San Diego, CA, USA), following standard protocols supplied by the manufacturer. Data were extracted from the GenomeStudio software (Illumina), and subsequently normalized and segmented using thresholded quantile normalization (tQN) and BAFsegmentation, respectively (Staaf et al. Normalization of array-CGH data: influence of copy number imbalances. BMC Genomics 2007, 8:382; Staaf et al. Segmentation-based detection of allelic imbalance and loss-of-heterozygosity in cancer cells using whole genome SNP arrays. Genome Biol 2008, 9:R136). Base pair positions are indicated according to the NCBI build 36 (hg18).

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Retained heterodisomy is associated with high gene expression in hyperhaploid inflammatory leiomyosarcoma (Illumina)

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