Author/Authors :
Dan A. Landau، نويسنده , , Scott L. Carter، نويسنده , , Petar Stojanov، نويسنده , , Aaron McKenna، نويسنده , , Kristen Stevenson، نويسنده , , Michael S. Lawrence، نويسنده , , Carrie Sougnez، نويسنده , , Chip Stewart، نويسنده , , Andrey Sivachenko، نويسنده , , Lili Wang، نويسنده , , Youzhong Wan، نويسنده , , Wandi Zhang، نويسنده , , Sachet A. Shukla، نويسنده , , Alexander Vartanov، نويسنده , , Stacey M. Fernandes، نويسنده , , Gordon Saksena، نويسنده , , Kristian Cibulskis، نويسنده , , Bethany Tesar، نويسنده , , Stacey Gabriel، نويسنده , , Nir Hacohen، نويسنده , , et al.، نويسنده ,
Abstract :
Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.
