title: Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation.
abstract: The pathogenesis of chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is still largely unknown. The full spectrum of genetic lesions that are present in the CLL genome, and therefore the number and identity of dysregulated cellular pathways, have not been identified. By combining next-generation sequencing and copy number analysis, we show here that the typical CLL coding genome contains <20 clonally represented gene alterations/case, including predominantly nonsilent mutations, and fewer copy number aberrations. These analyses led to the discovery of several genes not previously known to be altered in CLL. Although most of these genes were affected at low frequency in an expanded CLL screening cohort, mutational activation of NOTCH1, observed in 8.3% of CLL at diagnosis, was detected at significantly higher frequency during disease progression toward Richter transformation (31.0%), as well as in chemorefractory CLL (20.8%). Consistent with the association of NOTCH1 mutations with clinically aggressive forms of the disease, NOTCH1 activation at CLL diagnosis emerged as an independent predictor of poor survival. These results provide initial data on the complexity of the CLL coding genome and identify a dysregulated pathway of diagnostic and therapeutic relevance.
authors.affiliation: Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fabbri
authors.forename: Silvia
authors.initials: S
authors.lastname: Rasi
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trifonov
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Adina
authors.initials: A
authors.lastname: Grunn
authors.forename: Marco
authors.initials: M
authors.lastname: Fangazio
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Sara
authors.initials: S
authors.lastname: Monti
authors.forename: Stefania
authors.initials: S
authors.lastname: Cresta
authors.forename: Ernesto
authors.initials: E
authors.lastname: Gargiulo
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.forename: Luca
authors.initials: L
authors.lastname: Arcaini
authors.forename: Marco
authors.initials: M
authors.lastname: Paulli
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.forename: Luigi M
authors.initials: LM
authors.lastname: Larocca
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Robin
authors.initials: R
authors.lastname: Foá
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
mesh_terms: D000328:Adult; D000368:Aged; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D050438:Genes, Immunoglobulin Heavy Chain; D015894:Genome, Human; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics*; D017211:Treatment Failure
chemical_list: C497761:NOTCH1 protein, human; D051881:Receptor, Notch1