title: The routes for transformation of follicular lymphoma.
abstract: Aggressive transformation, a frequent event in the natural history of follicular lymphoma, is associated with increased lymphoma-related mortality and yet the underlying biology remains poorly defined. This review outlines recent advances in our understanding of the genetic basis and evolutionary process leading to transformation.
  
  
  
  Both the antecedent indolent and transformed follicular lymphoma (tFL) arise through branched divergent evolution with tumors emerging from a founder precursor population, the common progenitor cell. Although the majority of tFLs maintain a germinal center B-cell gene expression signature, an activated B-cell-type (ABC-type) profile appears to predominate in BCL2-translocation negative cases. It does not appear that a single unifying genetic or epigenetic event promotes a fitter and more aggressive clone.
  
  
  
  Transformed follicular tumors are genetically heterogeneous perhaps reflecting the varying clinical behavior and outcomes of this disease event. Follicular lymphoma and tFL remain incurable tumors highlighted by our inability to eradicate the founder common progenitor cell population with current therapies. Progress has now been made in defining the genetic events and evolutionary pathways responsible for transformation. Although more research is required in predicting and understanding the biology of transformation, there are opportunities to improve outcomes by preferentially directing targeted therapies toward 'actionable' early and transformation-specific aberrations.
authors.affiliation: aCentre for Haemato-Oncology, Barts Cancer Institute bDepartment of Haemato-oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Okosun
authors.forename: Silvia
authors.initials: S
authors.lastname: Montoto
authors.forename: Jude
authors.initials: J
authors.lastname: Fitzgibbon
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D060965:Clonal Evolution; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008224:Lymphoma, Follicular / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D009154:Mutation