Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome

Richter syndrome (RS) evolving from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that arises from an indolent or chronic cancer. Until recently, little was known about the molecular basis of this transformation from CLL to RS. To identify the genetic events that lead to the transformation of CLL to RS, we examined paired CLL and RS samples from a cohort of 52 patients with RS by whole exome sequencing and applied computational methods to separate out the RS and CLL DNA alterations. Our work uncovered recurrent genetic alterations in RS, including gene mutations, copy number alterations, whole genome doubling and chromothripsis, which was then confirmed in an independent validation cohort. We demonstrated that RS is largely different from DLBCL based on genetics, identified signaling pathways that are dysregulated in RS cells compared to CLL cells, and traced evolution to RS at a single-cell level. Our study identified genetic subtypes within RS and showed that RS DNA alterations can be detected in plasma samples, distinct from blood CLL cells, which may be a potential method for early diagnosis or detection of RS.