According to the identical immunoglobulin heavy-chain variable region (IGHV) rearrangement found in both CLL and RS cells, Richter syndrome (RS) is mostly caused by the direct transformation of the chronic lymphocytic leukemia (CLL) clone. Rare instances with better outcomes have an IGHV rearrangement that is distinct from the CLL phase in the RS clone. For a study, researchers sought to determine if the RS clone was already visible before clinicopathologic transition while being undetectable by traditional methods.

They looked at the CLL phase of clonally unrelated RS. Eight patients with unrelated RS had their CLL cells analyzed using an ultra-deep next-generation sequencing (NGS) method that has a sensitivity of 10-6. The RS rearrangement was not discovered in the CLL phase in 7 out of 8 patients. In one instance, the concomitance of CLL sampling and RS diagnosis led to the RS clone being discovered at a very low frequency in the CLL phase.

Targeted resequencing demonstrated that the genetic lesions in clonally unrelated RS are largely in the TP53, MYC, ATM, and NOTCH1 genes. In contrast, there were no mutations that were typically present in diffuse large B-cell lymphoma (DLBCL) that develop without a prior history of CLL. These findings imply that clonally unrelated RS is a really de novo lymphoma with a mutational signature that is, at least partially, similar to clonally related RS.