Clonal Evolution Affects Clinical Outcome in CLL

Genetic evolution of heterogeneous subclones within a tumor modulates cancer progression and is thought to contribute to disease relapse following therapy. However, the dynamics of this process are not well studied, and the importance of subclonal mutations in clinical outcome is unknown. Landau and colleagues assessed clonal evolution in chronic lymphocytic leukemia (CLL), a highly variable, slow-growing B-cell malignancy, using large-scale whole-exome sequencing and analysis of somatic copy number alterations in a large cohort of paired CLL and normal samples. This integrated approach identified 5 recurrent chromosomal abnormalities and recurrent somatic mutations in 20 putative CLL driver genes, including several previously unreported genes. Mutations that occurred in the majority of cancer cells were classified as clonal and represented early events in CLL development, including passenger events and B-cell–specific driver mutations in myeloid differentiation primary response 88 (MYD88), trisomy 12, and deletion of chromosome 13q. In contrast, subclonal mutations acquired after tumor initiation were detected in only a subset of leukemic cells and included alterations in known cancer genes such as TP53 and ataxia telangiectasia mutated (ATM). Intriguingly, the number of subclonal but not that of clonal mutations was increased in patients who had received prior chemotherapy compared with untreated patients, suggesting that treatment may facilitate the outgrowth of preexisting, highly fit subclones. In support of this idea, expansion of subclonal driver mutations was detected in 10 of 12 patients following chemotherapy compared with matched pretreatment samples, whereas clonal equilibrium predominated in untreated sample pairs. Furthermore, the presence of subclonal driver mutations prior to therapy was associated with increased risk of earlier disease progression independent of established prognostic markers. These results demonstrate that clonal evolution promotes stepwise CLL progression and drives tumor relapse after therapy.

Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, et al. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 2013;152:714–26.

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