title: Clinical, molecular, and prognostic significance of WHO type inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q abnormalities in acute myeloid leukemia.
abstract: OBJECTIVE
  Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) [inv(3)/t(3;3)] is recognized as a distinctive entity in the WHO classification. Risk assignment and clinical and genetic characterization of AML with chromosome 3q abnormalities other than inv(3)/t(3;3) remain largely unresolved.
  
  
  METHODS
  Cytogenetics, molecular genetics, therapy response, and outcome analysis were performed in 6,515 newly diagnosed adult AML patients. Patients were treated on Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research (HOVON/SAKK; n = 3,501) and German-Austrian Acute Myeloid Leukemia Study Group (AMLSG; n = 3,014) protocols. EVI1 and MDS1/EVI1 expression was determined by real-time quantitative polymerase chain reaction.
  
  
  RESULTS
  3q abnormalities were detected in 4.4% of AML patients (288 of 6,515). Four distinct groups were defined: A: inv(3)/t(3;3), 32%; B: balanced t(3q26), 18%; C: balanced t(3q21), 7%; and D: other 3q abnormalities, 43%. Monosomy 7 was the most common additional aberration in groups (A), 66%; (B), 31%; and (D), 37%. N-RAS mutations and dissociate EVI1 versus MDS1/EVI1 overexpression were associated with inv(3)/t(3;3). Patients with inv(3)/t(3;3) and balanced t(3q21) at diagnosis presented with higher WBC and platelet counts. In multivariable analysis, only inv(3)/t(3;3), but not t(3q26) and t(3q21), predicted reduced relapse-free survival (hazard ratio [HR], 1.99; P < .001) and overall survival (HR, 1.4; P = .006). This adverse prognostic impact of inv(3)/t(3;3) was enhanced by additional monosomy 7. Group D 3q aberrant AML also had a poor outcome related to the coexistence of complex and/or monosomal karyotypes and cryptic inv(3)/t(3;3).
  
  
  CONCLUSIONS
  Various categories of 3q abnormalities in AML can be distinguished according to their clinical, hematologic, and genetic features. AML with inv(3)/t(3;3) represents a distinctive subgroup with unfavorable prognosis.
authors.affiliation: Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Lugthart
authors.forename: Stefan
authors.initials: S
authors.lastname: Gröschel
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Sabine
authors.initials: S
authors.lastname: Kayser
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Valk
authors.forename: Shama Lydia
authors.initials: SL
authors.lastname: van Zelderen-Bhola
authors.forename: Gert
authors.initials: G
authors.lastname: Jan Ossenkoppele
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.forename: Eva
authors.initials: E
authors.lastname: van den Berg-de Ruiter
authors.forename: Urs
authors.initials: U
authors.lastname: Schanz
authors.forename: Gregor
authors.initials: G
authors.lastname: Verhoef
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Augustin
authors.initials: A
authors.lastname: Ferrant
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Heinz A
authors.initials: HA
authors.lastname: Horst
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Koller
authors.forename: Marie
authors.initials: M
authors.lastname: von Lilienfeld-Toal
authors.forename: Martin
authors.initials: M
authors.lastname: Bentz
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Martine
authors.initials: M
authors.lastname: Jotterand
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Thomas
authors.initials: T
authors.lastname: Pabst
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002869:Chromosome Aberrations; D007446:Chromosome Inversion; D002893:Chromosomes, Human, Pair 3; D002986:Clinical Trials as Topic; D004268:DNA-Binding Proteins; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D009006:Monosomy; D015999:Multivariate Analysis; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D016017:Odds Ratio; D011237:Predictive Value of Tests; D011379:Prognosis; D011519:Proto-Oncogenes; D012074:Remission Induction; D014157:Transcription Factors; D014178:Translocation, Genetic; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C484449:EVL protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors