title: Molecular ontogeny of donor-derived follicular lymphomas occurring after hematopoietic cell transplantation.
abstract: The relative timing of genetic alterations that contribute to follicular lymphoma remains unknown. We analyzed a donor-recipient pair who both developed grade 2/3A follicular lymphoma 7 years after allogeneic transplantation and donor lymphocyte infusions. Both patients harbored identical BCL2/IGH rearrangements also present in 1 in 2,000 cells in the donor lymphocyte infusion, and the same V(D)J rearrangement, which underwent somatic hypermutation both before and after clonal divergence. Exome sequencing of both follicular lymphomas identified 15 shared mutations, of which 14 (including alterations in EP300 and KLHL6) were recovered from the donor lymphocyte infusion by ultra-deep sequencing (average read coverage, 361,723), indicating acquisition at least 7 years before clinical presentation. Six additional mutations were present in only one follicular lymphoma and not the donor lymphocyte infusion, including an ARID1A premature stop, indicating later acquisition during clonal divergence. Thus, ultrasensitive sequencing can map clonal evolution within rare subpopulations during human lymphomagenesis in vivo.
  
  
  CONCLUSIONS
  For the first time, we define the molecular ontogeny of follicular lymphoma during clonal evolution in vivo. By using ultrasensitive mutation detection, we mapped the time-course of somatic alterations after passage of a malignant ancestor by hematopoietic cell transplantation.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Weigert
authors.forename: Nadja
authors.initials: N
authors.lastname: Kopp
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lane
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Anita Y
authors.initials: AY
authors.lastname: Bahar
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Janina A
authors.initials: JA
authors.lastname: Longtine
authors.forename: Frank C
authors.initials: FC
authors.lastname: Kuo
authors.forename: Terry
authors.initials: T
authors.lastname: Haley
authors.forename: Maura
authors.initials: M
authors.lastname: Salois
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sullivan
authors.forename: David C
authors.initials: DC
authors.lastname: Fisher
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fox
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
mesh_terms: D000328:Adult; D003001:Cloning, Molecular; D005260:Female; D005803:Genes, Immunoglobulin; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D019520:Living Donors; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic; D060152:V(D)J Recombination