Genetic and epigenetic profiling of CLL disease progression reveals limited somatic evolution and suggests a relationship to memory-cell development

E N Smith; E M Ghia; C M DeBoever; L Z Rassenti; K Jepsen; K-A Yoon; H Matsui; S Rozenzhak; H Alakus; P J Shepard; Y Dai; M Khosroheidari; M Bina; K L Gunderson; K Messer; L Muthuswamy; T J Hudson; O Harismendy; C L Barrett; C H M Jamieson; D A Carson; T J Kipps; K A Frazer

doi:10.1038/bcj.2015.14

Genetic and epigenetic profiling of CLL disease progression reveals limited somatic evolution and suggests a relationship to memory-cell development

Blood Cancer J. 2015 Apr 10;5(4):e303. doi: 10.1038/bcj.2015.14.

Authors

E N Smith¹, E M Ghia², C M DeBoever³, L Z Rassenti², K Jepsen⁴, K-A Yoon⁵, H Matsui⁶, S Rozenzhak¹, H Alakus¹, P J Shepard¹, Y Dai¹, M Khosroheidari⁴, M Bina⁷, K L Gunderson⁸, K Messer⁹, L Muthuswamy¹⁰, T J Hudson¹¹, O Harismendy¹, C L Barrett¹, C H M Jamieson¹², D A Carson², T J Kipps², K A Frazer¹³

Affiliations

¹ 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.
² 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 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.
⁵ Pediatrics and Rady's Children's Hospital, University of California at San Diego, La Jolla, CA, USA.
⁶ 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.
⁷ Department of Chemistry, Purdue University, West Lafayette, IN, USA.
⁸ Illumina, Inc., 5200 Illumina Way, San Diego, CA, USA.
⁹ Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA.
¹⁰ 1] Ontario Institute for Cancer Research, Toronto, Ontario, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
¹¹ 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.
¹² 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.
¹³ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Clonal Evolution / genetics*
CpG Islands / genetics
DNA Methylation / genetics*
Disease Progression
Epigenesis, Genetic*
Humans
Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
Leukemia, Lymphocytic, Chronic, B-Cell / pathology
Mutation
Polycomb-Group Proteins / genetics

Substances

Polycomb-Group Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding