Dataset Information

Genome-Wide Analysis of Hypodiploid Acute Lymphoblastic Leukemia

ABSTRACT:

Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive form of leukemia characterized by multiple whole chromosomal losses and very poor outcome. Here we report an integrative genomic analysis that identifies multiple subtypes of hypodiploid ALL characterized by variation in the degree of aneuploidy, distinct submicroscopic deletions and sequence mutations and gene expression profile. Near haploid ALL cases (24-31 chromosomes) have a high frequency of alterations of genes regulating Ras pathway and cytokine receptor signaling (66.2%; NF1, NRAS, KRAS, PTPN11, FLT3, and PAG1), IKZF3 (encoding the lymphoid transcription factor AIOLOS), and a histone gene cluster at 6p22. Low hypodiploid cases (32-39 chromosomes) are enriched for IKZF2 (HELIOS) and RB1 alterations, but have a low frequency of Ras/signaling alterations. A striking finding was exclusivity of Ras/signaling and IKZF2/3 alterations, and biochemical evidence of Ras pathway activation in both near haploid and low hypodiploid ALL. Together, these findings provide critical new insights into the genetic basis of hypodiploid ALL, and indicate that therapeutic targeting of the Ras pathway should be pursued in this disease.

PROVIDER: phs000341.v1.p1 | EGA |

REPOSITORIES: EGA

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Publications

The genomic landscape of hypodiploid acute lymphoblastic leukemia.

Holmfeldt Linda L Wei Lei L Diaz-Flores Ernesto E Walsh Michael M Zhang Jinghui J Ding Li L Payne-Turner Debbie D Churchman Michelle M Andersson Anna A Chen Shann-Ching SC McCastlain Kelly K Becksfort Jared J Ma Jing J Wu Gang G Patel Samir N SN Heatley Susan L SL Phillips Letha A LA Song Guangchun G Easton John J Parker Matthew M Chen Xiang X Rusch Michael M Boggs Kristy K Vadodaria Bhavin B Hedlund Erin E Drenberg Christina C Baker Sharyn S Pei Deqing D Cheng Cheng C Huether Robert R Lu Charles C Fulton Robert S RS Fulton Lucinda L LL Tabib Yashodhan Y Dooling David J DJ Ochoa Kerri K Minden Mark M Lewis Ian D ID To L Bik LB Marlton Paula P Roberts Andrew W AW Raca Gordana G Stock Wendy W Neale Geoffrey G Drexler Hans G HG Dickins Ross A RA Ellison David W DW Shurtleff Sheila A SA Pui Ching-Hon CH Ribeiro Raul C RC Devidas Meenakshi M Carroll Andrew J AJ Heerema Nyla A NA Wood Brent B Borowitz Michael J MJ Gastier-Foster Julie M JM Raimondi Susana C SC Mardis Elaine R ER Wilson Richard K RK Downing James R JR Hunger Stephen P SP Loh Mignon L ML Mullighan Charles G CG

Nature genetics 20130120 3

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signali ...[more]

PMID: 23334668

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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).

Project description:Recurrent non-medullary thyroid carcinoma (NMTC) is a rare disease. We initially characterized 27 recurrent NMTC: 13 papillary thyroid cancers (PTC), 10 oncocytic follicular carcinomas (FTC-OV), and 4 non-oncocytic follicular carcinomas (FTC). A validation cohort composed of benign and malignant (both recurrent and non-recurrent) thyroid tumours was subsequently analysed (n = 20). Methods Data from genome-wide SNP arrays and flow cytometry were combined to determine the chromosomal dosage (allelic state) in these tumours, including mutation analysis of components of PIK3CA/AKT and MAPK pathways. Results All FTC-OVs showed a very distinct pattern of genomic alterations. Ten out of 10 FTC-OV cases showed near-haploidisation with or without subsequent genome endoreduplication. Near-haploidisation was seen in 5/10 as extensive chromosome-wide monosomy (allelic state [A]) with near-haploid DNA indices and retention of especially chromosome 7 (seen as a heterozygous allelic state [AB]). In the remaining 5/10 chromosomal allelic states AA with near diploid DNA indices were seen with allelic state AABB of chromosome 7, suggesting endoreduplication after preceding haploidisation. The latter was supported by the presence of both near-haploid and endoreduplicated tumour fractions in some of the cases. Results were confirmed using FISH analysis. Relatively to FTC-OV limited numbers of genomic alterations were identified in other types of recurrent NMTC studied, except for chromosome 22q which showed alterations in 6 of 13 PTCs. Only two HRAS, but no mutations of EGFR or BRAF were found in FTC-OV. The validation cohort showed two additional tumours with the distinct pattern of genomic alterations (both with oncocytic features and recurrent). Conclusions We demonstrate that recurrent FTC-OV is frequently characterised by genome-wide DNA haploidisation, heterozygous retention of chromosome 7, and endoreduplication of a near-haploid genome. Whether normal gene dosage on especially chromosome 7 (containing EGFR, BRAF, cMET) is crucial for FTC-OV tumour survival is an important topic for future research. 28 thyroid tumors from 27 patients were profiled by SNP array. Comparisons between different types were made.

Dataset Information

Genome-Wide Analysis of Hypodiploid Acute Lymphoblastic Leukemia

Publications

The genomic landscape of hypodiploid acute lymphoblastic leukemia.

Similar Datasets

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