Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia

Juhi Ojha, Jackline Ayres, Charla Secreto, Renee Tschumper, Kari Rabe, Daniel Van Dyke, Susan Slager, Tait Shanafelt, Rafael Fonseca, Neil E. Kay and Esteban Braggio

Key Points

  • Deep sequencing identifies a significant reservoir of subclonal mutations affecting key genes in CLL pathogenesis.

  • Convergent evolution of genetic lesions in tumor subclonal populations is recurrently found in CLL.


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.

  • Submitted June 13, 2014.
  • Accepted November 2, 2014.
View Full Text