title: t(14;18) Translocation: A predictive blood biomarker for follicular lymphoma.
abstract: OBJECTIVE
  The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL.
  
  
  METHODS
  Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction-based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples.
  
  
  RESULTS
  Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10(-4) (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis.
  
  
  CONCLUSIONS
  High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.
authors.affiliation: Sandrine Roulland, Ester Morgado, Stéphanie Sungalee, Nathalie Jouve, and Bertrand Nadel, Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM) U1104, and Centre National de la Recherche Scientifique (CNRS) Unités Mixtes de Recherche (UMR) 7280, Marseille; Philippe Solal-Celigny, Jean Bernard Center, Le Mans; Philippe Colombat, Bretonneau University Hospital, Tours; Françoise Clavel-Chapelon, INSERM U1018 Centre de Recherche en Epidémiologie et Santé des Populations, Villejuif; Pietro Ferrari and Isabelle Romieu, International Agency for Research on Cancer, Lyon; Gilles Salles, Hospices Civils de Lyon, Université de Lyon, UMR CNRS 5239, Pierre Bénite, France; Rachel S. Kelly, Petra H.M. Peeters, Roel Vermeulen, Elio Riboli, and Paolo Vineis, School of Public Health, Imperial College London, London; Kay-Tee Khaw, University of Cambridge; Nick Wareham, Institute of Metabolic Science, Cambridge; Timothy J. Key and Ruth C. Travis, University of Oxford, Oxford, United Kingdom; Domenico Palli, Istituto per lo Studio e la Prevenzione Oncologica, Florence; Valeria Pala, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan; Rosario Tumino, "Civile-M.P. Arezzo" Hospital, Ragusa; Salvatore Panico, Federico II University, Naples; Carlotta Sacerdote, Centro di Riferimento per l'Epidemiologia e la Prevenzione Oncologica-Piemonte, Torino, Italy; José R. Quirós, Public Health and Health Planning Directorate, Asturias; Carlos A. Gonzáles, Catalan Institute of Oncology, Barcelona; Maria-José Sánchez, Andalusian School of Public Health and Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Granada; Miren Dorronsoro, Basque Regional Health Department and CIBERESP Biodonostia, San Sebastian; Carmen Navarro, Murcia Regional Health Council, Universidad de Murcia, and CIBERESP, Murcia; Aurelio Barricarte, Navarre Public Health Institute and CIBERESP, Pamplona, Sp
authors.forename: Sandrine
authors.initials: S
authors.lastname: Roulland
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Kelly
authors.forename: Ester
authors.initials: E
authors.lastname: Morgado
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sungalee
authors.forename: Philippe
authors.initials: P
authors.lastname: Solal-Celigny
authors.forename: Philippe
authors.initials: P
authors.lastname: Colombat
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jouve
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.forename: Valeria
authors.initials: V
authors.lastname: Pala
authors.forename: Rosario
authors.initials: R
authors.lastname: Tumino
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panico
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.forename: José R
authors.initials: JR
authors.lastname: Quirós
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Gonzáles
authors.forename: Maria-José
authors.initials: MJ
authors.lastname: Sánchez
authors.forename: Miren
authors.initials: M
authors.lastname: Dorronsoro
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarro
authors.forename: Aurelio
authors.initials: A
authors.lastname: Barricarte
authors.forename: Anne
authors.initials: A
authors.lastname: Tjønneland
authors.forename: Anja
authors.initials: A
authors.lastname: Olsen
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kaaks
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: Dagmar
authors.initials: D
authors.lastname: Drogan
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nieters
authors.forename: Françoise
authors.initials: F
authors.lastname: Clavel-Chapelon
authors.forename: Antonia
authors.initials: A
authors.lastname: Trichopoulou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Trichopoulos
authors.forename: Pagona
authors.initials: P
authors.lastname: Lagiou
authors.forename: H Bas
authors.initials: HB
authors.lastname: Bueno-de-Mesquita
authors.forename: Petra H M
authors.initials: PH
authors.lastname: Peeters
authors.forename: Roel
authors.initials: R
authors.lastname: Vermeulen
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.forename: Beatrice
authors.initials: B
authors.lastname: Melin
authors.forename: Signe
authors.initials: S
authors.lastname: Borgquist
authors.forename: Joyce
authors.initials: J
authors.lastname: Carlson
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.forename: Elisabete
authors.initials: E
authors.lastname: Weiderpass
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Nick
authors.initials: N
authors.lastname: Wareham
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Key
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Travis
authors.forename: Pietro
authors.initials: P
authors.lastname: Ferrari
authors.forename: Isabelle
authors.initials: I
authors.lastname: Romieu
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.forename: Bertrand
authors.initials: B
authors.lastname: Nadel
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D016022:Case-Control Studies; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D015331:Cohort Studies; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D008224:Lymphoma, Follicular / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D016133:Polymerase Chain Reaction / Q000379:methods; D015995:Prevalence; D014178:Translocation, Genetic
chemical_list: D014408:Biomarkers, Tumor