title: Genetic and epigenetic profiling of CLL disease progression reveals limited somatic evolution and suggests a relationship to memory-cell development.
abstract: We examined genetic and epigenetic changes that occur during disease progression from indolent to aggressive forms of chronic lymphocytic leukemia (CLL) using serial samples from 27 patients. Analysis of DNA mutations grouped the leukemia cases into three categories: evolving (26%), expanding (26%) and static (47%). Thus, approximately three-quarters of the CLL cases had little to no genetic subclonal evolution. However, we identified significant recurrent DNA methylation changes during progression at 4752 CpGs enriched for regions near Polycomb 2 repressive complex (PRC2) targets. Progression-associated CpGs near the PRC2 targets undergo methylation changes in the same direction during disease progression as during normal development from naive to memory B cells. Our study shows that CLL progression does not typically occur via subclonal evolution, but that certain CpG sites undergo recurrent methylation changes. Our results suggest CLL progression may involve developmental processes shared in common with the generation of normal memory B cells.
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors: E N
authors: EN
authors: Smith
authors: 1] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA [2] Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
authors: E M
authors: EM
authors: Ghia
authors: Bioinformatics and Systems Biology Program, University of California at San Diego, La Jolla, CA, USA.
authors: C M
authors: CM
authors: DeBoever
authors: 1] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA [2] Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
authors: L Z
authors: LZ
authors: Rassenti
authors: Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA.
authors: K
authors: K
authors: Jepsen
authors: Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA.
authors: K-A
authors: KA
authors: Yoon
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA.
authors: H
authors: H
authors: Matsui
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors: S
authors: S
authors: Rozenzhak
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors: H
authors: H
authors: Alakus
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors: P J
authors: PJ
authors: Shepard
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors: Y
authors: Y
authors: Dai
authors: Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA.
authors: M
authors: M
authors: Khosroheidari
authors: Department of Chemistry, Purdue University, West Lafayette, IN, USA.
authors: M
authors: M
authors: Bina
authors: Illumina, Inc., 5200 Illumina Way, San Diego, CA, USA.
authors: K L
authors: KL
authors: Gunderson
authors: Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors: K
authors: K
authors: Messer
authors: 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
authors: L
authors: L
authors: Muthuswamy
authors: 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada [3] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors: T J
authors: TJ
authors: Hudson
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors: O
authors: O
authors: Harismendy
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
authors: C L
authors: CL
authors: Barrett
authors: 1] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA [2] Department of Medicine, University of California at San Diego, La Jolla, CA, USA [3] Stem Cell Program, University of California San Diego, La Jolla, CA, USA.
authors: C H M
authors: CH
authors: Jamieson
authors: 1] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA [2] Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
authors: D A
authors: DA
authors: Carson
authors: 1] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA [2] Department of Medicine, University of California at San Diego, La Jolla, CA, USA.
authors: T J
authors: TJ
authors: Kipps
authors: 1] Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA [2] Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA [3] Bioinformatics and Systems Biology Program, University of California at San Diego, La Jolla, CA, USA [4] Institute for Genomic Medicine, University of California at San Diego, La Jolla, CA, USA.
authors: K A
authors: KA
authors: Frazer
mesh_terms: D060965:Clonal Evolution / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D044127:Epigenesis, Genetic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D063146:Polycomb-Group Proteins / Q000235:genetics
chemical_list: D063146:Polycomb-Group Proteins