title: Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia.
abstract: The identification of new genetic lesions in chronic lymphocytic leukemia (CLL) prompts a comprehensive and dynamic prognostic algorithm including gene mutations and chromosomal abnormalities and their changes during clonal evolution. By integrating mutational and cytogenetic analysis in 1274 CLL samples and using both a training-validation and a time-dependent design, 4 CLL subgroups were hierarchically classified: (1) high-risk, harboring TP53 and/or BIRC3 abnormalities (10-year survival: 29%); (2) intermediate-risk, harboring NOTCH1 and/or SF3B1 mutations and/or del11q22-q23 (10-year survival: 37%); (3) low-risk, harboring +12 or a normal genetics (10-year survival: 57%); and (4) very low-risk, harboring del13q14 only, whose 10-year survival (69.3%) did not significantly differ from a matched general population. This integrated mutational and cytogenetic model independently predicted survival, improved CLL prognostication accuracy compared with FISH karyotype (P < .0001), and was externally validated in an independent CLL cohort. Clonal evolution from lower to higher risk implicated the emergence of NOTCH1, SF3B1, and BIRC3 abnormalities in addition to TP53 and 11q22-q23 lesions. By taking into account clonal evolution through time-dependent analysis, the genetic model maintained its prognostic relevance at any time from diagnosis. These findings may have relevant implications for the design of clinical trials aimed at assessing the use of mutational profiling to inform therapeutic decisions.
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy. rossidav@med.unipmn.it
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Silvia
authors.initials: S
authors.lastname: Rasi
authors.forename: Valeria
authors.initials: V
authors.lastname: Spina
authors.forename: Alessio
authors.initials: A
authors.lastname: Bruscaggin
authors.forename: Sara
authors.initials: S
authors.lastname: Monti
authors.forename: Carmela
authors.initials: C
authors.lastname: Ciardullo
authors.forename: Clara
authors.initials: C
authors.lastname: Deambrogi
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.forename: Roberto
authors.initials: R
authors.lastname: Serra
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.forename: Michele
authors.initials: M
authors.lastname: Dal-Bo
authors.forename: Francesca Maria
authors.initials: FM
authors.lastname: Rossi
authors.forename: Pietro
authors.initials: P
authors.lastname: Bulian
authors.forename: Josep
authors.initials: J
authors.lastname: Nomdedeu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
mesh_terms: D000465:Algorithms; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D004252:DNA Mutational Analysis; D004502:Education, Medical, Continuing; D005260:Female; D005820:Genetic Testing; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008957:Models, Genetic; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D011379:Prognosis; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
chemical_list: D051034:Inhibitor of Apoptosis Proteins; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C497761:NOTCH1 protein, human; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases