Richter syndrome (RS) is mostly due to the direct transformation of the chronic lymphocytic leukaemia (CLL) clone, as documented by the same immunoglobulin heavy-chain variable region (IGHV) rearrangement in both CLL and RS cells.In rare cases characterized by a better outcome, the RS clone harbours a different IGHV rearrangement compared to the CLL phase. We investigated the CLL phase of clonally unrelated RS to test whether the RS clone was already identifiable prior to clinicopathologic transformation, albeit undetectable by conventional approaches. CLL cells of eight patients with unrelated RS were subjected to an ultra-deep nextgeneration sequencing (NGS) approach with a sensitivity of 10 −6 . In 7/8 cases, the RS rearrangement was not identified in the CLL phase. In one case, the RS clone was identified at a very low frequency in the CLL phase, conceivably due to the concomitance of CLL sampling and RS diagnosis. Targeted resequencing revealed that clonally unrelated RS carries genetic lesions primarily affecting the TP53, MYC, ATM and NOTCH1 genes. Conversely, mutations frequently involved in de novo diffuse large B-cell lymphoma (DLBCL) without a history of CLL were absent. These results suggest that clonally unrelated RS is a truly de novo lymphoma with a mutational profile reminiscent, at least in part, of clonally related RS.
We aimed at molecularly dissecting the anatomical heterogeneity of small lymphocytic lymphoma (SLL), by analysing a cohort of 12 patients for whom paired DNA from a lymph node biopsy and circulating cells, as well as plasma-circulating tumour DNA (ctDNA) was available. Notably, the analyses of the lymph node biopsy and of circulating cells complement each other since a fraction of mutations (20Á4% and 36Á4%, respectively) are unique to each compartment. Plasma ctDNA identified two additional unique mutations. Consistently, the different synchronous sources of tumour DNA complement each other in informing on driver gene mutations in SLL harbouring potential prognostic and/or predictive value.
The assessment of the cancer mutational profile is crucial for patient management, stratification, and therapeutic decisions. At present, in hematological malignancies with a solid mass, such as lymphomas, tumor genomic profiling is generally performed on the tissue biopsy, but the tumor may harbor genetic lesions that are unique to other anatomical compartments. The analysis of circulating tumor DNA (ctDNA) on the liquid biopsy is an emerging approach that allows genotyping and monitoring of the disease during therapy and follow-up. This review presents the different methods for ctDNA analysis and describes the application of liquid biopsy in different hematological malignancies. In diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), ctDNA analysis on the liquid biopsy recapitulates the mutational profile of the tissue biopsy and can identify mutations otherwise absent on the tissue biopsy. In addition, changes in the ctDNA amount after one or two courses of chemotherapy significantly predict patient outcomes. ctDNA analysis has also been tested in myeloid neoplasms with promising results. In addition to mutational analysis, liquid biopsy also carries potential future applications of ctDNA, including the analysis of ctDNA fragmentation and epigenetic patterns. On these grounds, several clinical trials aiming at incorporating ctDNA analysis for treatment tailoring are currently ongoing in hematological malignancies.
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