TY - JOUR
T1 - Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia
AU - Ojha, Juhi
AU - Ayres, Jackline
AU - Secreto, Charla
AU - Tschumper, Renee
AU - Rabe, Kari
AU - Van Dyke, Daniel
AU - Slager, Susan
AU - Shanafelt, Tait
AU - Fonseca, Rafael
AU - Kay, Neil E.
AU - Braggio, Esteban
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015/1/15
Y1 - 2015/1/15
N2 - 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, includingmutations 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.
AB - 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, includingmutations 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.
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U2 - 10.1182/blood-2014-06-580563
DO - 10.1182/blood-2014-06-580563
M3 - Article
C2 - 25377784
AN - SCOPUS:84961289235
SN - 0006-4971
VL - 125
SP - 492
EP - 498
JO - Blood
JF - Blood
IS - 3
ER -