title: Chromosome aberrations detected by conventional karyotyping using novel mitogens in chronic lymphocytic leukemia: Clinical and biologic correlations.
abstract: To clarify whether karyotype aberrations (KA) involving regions not covered by the standard fluorescence in situ hybridization (FISH) panel have independent prognostic relevance, we evaluated KA by conventional cytogenetics in a learning cohort (LC; n = 166) and a validation cohort (VC; n = 250) of untreated chronic lymphocytic leukemia (CLL) patients. In the VC, novel mitogens were used to improve metaphase generation and TP53, NOTCH1, and SF3B1 mutations were assessed. KA undetected by FISH were found in 35 and 35% of the cases in the LC and VC, respectively. In addition to FISH, KA allowed reclassification of 23 and 26% of cases in the LC and VC, respectively, into a higher cytogenetic risk group. By multivariate analysis, both in the LC and VC, KA other than isolated 13q deletion correlated with a shorter time to first treatment (TFT; P < 0.001 and 0.003, respectively), while a complex karyotype predicted a worse overall survival (OS, P = 0.015 and 0.010, respectively). In the VC, where a comprehensive biologic assessment was performed, a shorter TFT was also predicted by stage (P < 0.001), IGHV mutational status (P = 0.05), and del(17p)/TP53 mutations (P = 0.033) while stage (P = 0.023) and del(17p)/TP53 mutations (P = 0.024) independently predicted a shorter OS. FISH results did not independently impact on TFT and OS, in the LC and VC cohorts; this was also the case for NOTCH1 and SF3B1 mutations in the VC. We suggest that in CLL, conventional karyotyping with novel mitogens could be more effective than FISH for the detection of KA allowing for a more precise refinement of prognosis.
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Gian Matteo
authors.initials: GM
authors.lastname: Rigolin
authors.affiliation: Section of Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I 'Sapienza' University, Roma, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: del Giudice
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Formigaro
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Saccenti
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Martinelli
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cavallari
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Lista
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Tammiso
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Volta
authors.affiliation: Department of Experimental and Diagnostic Medicine, "Laboratorio per Le Tecnologie Delle Terapie Avanzate" (LTTA), University of Ferrara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lupini
authors.affiliation: Department of Experimental and Diagnostic Medicine, "Laboratorio per Le Tecnologie Delle Terapie Avanzate" (LTTA), University of Ferrara, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bassi
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bardi
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Olga
authors.initials: O
authors.lastname: Sofritti
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Daghia
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavazzini
authors.affiliation: Section of Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I 'Sapienza' University, Roma, Italy.
authors.forename: Marilisa
authors.initials: M
authors.lastname: Marinelli
authors.affiliation: Section of Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I 'Sapienza' University, Roma, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Tavolaro
authors.affiliation: Section of Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I 'Sapienza' University, Roma, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.affiliation: Department of Experimental and Diagnostic Medicine, "Laboratorio per Le Tecnologie Delle Terapie Avanzate" (LTTA), University of Ferrara, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
authors.affiliation: Section of Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I 'Sapienza' University, Roma, Italy.
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.affiliation: Section of Hematology, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, University of Ferrara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuneo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003582:Cytogenetics; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D017404:In Situ Hybridization, Fluorescence; D007376:Interleukin-2 / Q000494:pharmacology*; D007621:Karyotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000494:pharmacology*; D015999:Multivariate Analysis; D009154:Mutation; D009841:Oligonucleotides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics; D011379:Prognosis; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D061665:Time-to-Treatment; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C539572:CpG-ODN DSP30; D007143:Immunoglobulin Heavy Chains; D007376:Interleukin-2; D008934:Mitogens; C497761:NOTCH1 protein, human; D009841:Oligonucleotides; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D011994:Recombinant Proteins; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53