title: Detection of chromothripsis-like patterns with a custom array platform for chronic lymphocytic leukemia.
abstract: Chronic lymphocytic leukemia (CLL) is a common disease with highly variable clinical course. Several recurrent chromosomal alterations are associated with prognosis and may guide risk-adapted therapy. We have developed a targeted genome-wide array to provide a robust tool for ascertaining abnormalities in CLL and to overcome limitations of the 4-marker fluorescence in situ hybridization (FISH). DNA from 180 CLL patients were hybridized to the qChip®Hemo array with a high density of probes covering commonly altered loci in CLL (11q22-q23, 13q14, and 17p13), nine focal regions (2p15-p16.1, 2p24.3, 2q13, 2q36.3-q37.1, 3p21.31, 8q24.21, 9p21.3, 10q24.32, and 18q21.32-q21.33) and two larger regions (6q14.1-q22.31 and 7q31.33-q33). Overall, 86% of the cases presented copy number alterations (CNA) by array. There was a high concordance of array findings with FISH (84% sensitivity, 100% specificity); all discrepancies corresponded to subclonal alterations detected only by FISH. A chromothripsis-like pattern was detected in eight cases. Three showed concomitant shattered 5p with gain of TERT along with isochromosome 17q. Presence of 11q loss was associated with shorter time to first treatment (P = 0.003), whereas 17p loss, increased genomic complexity, and chromothripsis were associated with shorter overall survival (P < 0.001, P = 0.001, and P = 0.02, respectively). In conclusion, we have validated a targeted array for the diagnosis of CLL that accurately detects, in a single experiment, all relevant CNAs, genomic complexity, chromothripsis, copy number neutral loss of heterozygosity, and CNAs not covered by the FISH panel. This test may be used as a practical tool to stratify CLL patients for routine diagnostics or clinical trials.
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Itziar
authors: I
authors: Salaverria
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: David
authors: D
authors: Martín-Garcia
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany.
authors: Cristina
authors: C
authors: López
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Guillem
authors: G
authors: Clot
authors: R&D, Department, Quantitative Genomic Medicine Laboratories (qGenomics), Barcelona, Spain.
authors: Manel
authors: M
authors: García-Aragonés
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Alba
authors: A
authors: Navarro
authors: Department of Hematology, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors: Julio
authors: J
authors: Delgado
authors: Department of Hematology, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors: Tycho
authors: T
authors: Baumann
authors: Genomics Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Magda
authors: M
authors: Pinyol
authors: Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany.|Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain.
authors: Idoia
authors: I
authors: Martin-Guerrero
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Ana
authors: A
authors: Carrió
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Dolors
authors: D
authors: Costa
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Ana C
authors: AC
authors: Queirós
authors: Ernest and Helen Scott Haematological Research Institute, Department of Biochemistry, University of Leicester, Leicester, UK.
authors: Sandrine
authors: S
authors: Jayne
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Marta
authors: M
authors: Aymerich
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Neus
authors: N
authors: Villamor
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Dolors
authors: D
authors: Colomer
authors: Department of Hematology, Hospital Clínico-IBSAL, Cancer Institute of Salamanca-IBMCC (USAL-CSIC), Salamanca, Spain.
authors: Marcos
authors: M
authors: González
authors: Department of Hematology, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors: Armando
authors: A
authors: López-Guillermo
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Elías
authors: E
authors: Campo
authors: Ernest and Helen Scott Haematological Research Institute, Department of Biochemistry, University of Leicester, Leicester, UK.
authors: Martin J S
authors: MJ
authors: Dyer
authors: Institute of Human Genetics, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrechts University, Kiel, Germany.
authors: Reiner
authors: R
authors: Siebert
authors: R&D, Department, Quantitative Genomic Medicine Laboratories (qGenomics), Barcelona, Spain.
authors: Lluís
authors: L
authors: Armengol
authors: Hematopathology Unit, Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors: Sílvia
authors: S
authors: Beà
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D005260:Female; D018628:Gene Dosage; D015894:Genome, Human; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods