title: Clonal evolution in t(14;18)-positive follicular lymphoma, evidence for multiple common pathways, and frequent parallel clonal evolution.
abstract: OBJECTIVE
  Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome.
  
  
  METHODS
  All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed.
  
  
  RESULTS
  Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances.
  
  
  CONCLUSIONS
  Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.
authors.affiliation: Department of Pathology and Microbiology, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: d'Amore
authors.forename: Eric
authors.initials: E
authors.lastname: Chan
authors.forename: Javeed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Ken
authors.initials: K
authors.lastname: Young
authors.forename: Li
authors.initials: L
authors.lastname: Xiao
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Hess
authors.forename: Warren G
authors.initials: WG
authors.lastname: Sanger
authors.forename: Lynette
authors.initials: L
authors.lastname: Smith
authors.forename: Carsten
authors.initials: C
authors.lastname: Wiuf
authors.forename: Oskar
authors.initials: O
authors.lastname: Hagberg
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Bhavana J
authors.initials: BJ
authors.lastname: Dave
mesh_terms: D002869:Chromosome Aberrations; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D002999:Clone Cells; D018450:Disease Progression; D006801:Humans; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D014178:Translocation, Genetic