Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia.
Recent high-throughput sequencing and microarray studies have characterized the genetic landscape and clonal complexity of chronic lymphocytic leukemia (CLL). Here, we performed a longitudinal study in a homogeneously treated cohort of 12 patients, with sequential samples obtained at comparable stages of disease. We identified clonal competition between 2 or more genetic subclones in 70% of the patients with relapse, and stable clonal dynamics in the remaining 30%. By deep sequencing, we identified a high reservoir of genetic heterogeneity in the form of several driver genes mutated in small subclones underlying the disease course. Furthermore, in 2 patients, we identified convergent evolution, characterized by the combination of genetic lesions affecting the same genes or copy number abnormality in different subclones. The phenomenon affects multiple CLL putative driver abnormalities, including mutations in NOTCH1, SF3B1, DDX3X, and del(11q23). This is the first report documenting convergent evolution as a recurrent event in the CLL genome. Furthermore, this finding suggests the selective advantage of specific combinations of genetic lesions for CLL pathogenesis in a subset of patients.
Mayo Clinic, Scottsdale, AZ;
Juhi
J
Ojha
National Institute of Cancer, Rio de Janeiro, Brazil; and.
Jackline
J
Ayres
Mayo Clinic, Rochester, MN.
Charla
C
Secreto
Mayo Clinic, Rochester, MN.
Renee
R
Tschumper
Mayo Clinic, Rochester, MN.
Kari
K
Rabe
Mayo Clinic, Rochester, MN.
Daniel
D
Van Dyke
Mayo Clinic, Rochester, MN.
Susan
S
Slager
Mayo Clinic, Rochester, MN.
Tait
T
Shanafelt
Mayo Clinic, Scottsdale, AZ;
Rafael
R
Fonseca
Mayo Clinic, Rochester, MN.
Neil E
NE
Kay
Mayo Clinic, Scottsdale, AZ;
Esteban
E
Braggio
D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D018450:Disease Progression; D019143:Evolution, Molecular; D005500:Follow-Up Studies; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000235:genetics*; D008137:Longitudinal Studies; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics*; D011379:Prognosis
D014408:Biomarkers, Tumor