Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns.
Chronic lymphocytic leukemia is characterized by relapse after treatment and chemotherapy resistance. Similarly, in other malignancies leukemia cells accumulate mutations during growth, forming heterogeneous cell populations that are subject to Darwinian selection and may respond differentially to treatment. There is therefore a clinical need to monitor changes in the subclonal composition of cancers during disease progression. Here, we use whole-genome sequencing to track subclonal heterogeneity in 3 chronic lymphocytic leukemia patients subjected to repeated cycles of therapy. We reveal different somatic mutation profiles in each patient and use these to establish probable hierarchical patterns of subclonal evolution, to identify subclones that decline or expand over time, and to detect founder mutations. We show that clonal evolution patterns are heterogeneous in individual patients. We conclude that genome sequencing is a powerful and sensitive approach to monitor disease progression repeatedly at the molecular level. If applied to future clinical trials, this approach might eventually influence treatment strategies as a tool to individualize and direct cancer treatment.
Oxford National Institute of Health Research NIHR Biomedical Research Centre, University of Oxford, Oxford OX3 9DS, United Kingdom. anna.schuh@ndcls.ox.ac.uk
Anna
A
Schuh
Jennifer
J
Becq
Sean
S
Humphray
Adrian
A
Alexa
Adam
A
Burns
Ruth
R
Clifford
Stephan M
SM
Feller
Russell
R
Grocock
Shirley
S
Henderson
Irina
I
Khrebtukova
Zoya
Z
Kingsbury
Shujun
S
Luo
David
D
McBride
Lisa
L
Murray
Toshi
T
Menju
Adele
A
Timbs
Mark
M
Ross
Jenny
J
Taylor
David
D
Bentley
D000483:Alleles; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D017637:Clonal Deletion; D002999:Clone Cells; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D019143:Evolution, Molecular; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins