The landscape of copy number variations in classical Hodgkin lymphoma: a joint KU Leuven and LYSA study on cell-free DNA

Abstract

The low abundance of Hodgkin/Reed-Sternberg (HRS) cells in lymph node biopsies in classical Hodgkin lymphoma (cHL) complicates the analysis of somatic genetic alterations in HRS cells. As circulating cell-free DNA (cfDNA) contains circulating tumor DNA (ctDNA) from HRS cells, we prospectively collected cfDNA from 177 patients with newly diagnosed, mostly early-stage cHL in a monocentric study at Leuven, Belgium (n = 59) and the multicentric BREACH study by Lymphoma Study Association (n = 118). To catalog the patterns and frequencies of genomic copy number aberrations (CNAs), cfDNA was sequenced at low coverage (0.26×), and data were analyzed with ichorCNA to yield read depth-based copy number profiles and estimated clonal fractions in cfDNA. At diagnosis, the cfDNA concentration, estimated clonal fraction, and ctDNA concentration were significantly higher in cHL cases than controls. More than 90% of patients exhibited CNAs in cfDNA. The most frequent gains encompassed 2p16 (69%), 5p14 (50%), 12q13 (50%), 9p24 (50%), 5q (44%), 17q (43%), 2q (41%). Losses mostly affected 13q (57%), 6q25-q27 (55%), 4q35 (50%), 11q23 (44%), 8p21 (43%). In addition, we identified loss of 3p13-p26 and of 12q21-q24 and gain of 15q21-q26 as novel recurrent CNAs in cHL. At diagnosis, ctDNA concentration was associated with advanced disease, male sex, extensive nodal disease, elevated erythrocyte sedimentation rate, metabolic tumor volume, and HRS cell burden. CNAs and ctDNA rapidly diminished upon treatment initiation, and persistence of CNAs was associated with increased probability of relapse. This study endorses the development of ctDNA as gateway to the HRS genome and substrate for early disease response evaluation.

Outcome of Children and Adolescents with Recurrent Classical Hodgkin Lymphoma: The Italian Experience

“…Moreover, it can monitor the quality of response detecting the minimal residual disease, or the recurrence of the disease. These new biomarkers should be considered among the future predictive features, considering the improving technology and the emerging results, even though the requirement of validation in prospective analyses in childhood cHL [17][18][19].…”

Application of precision medicine in clinical routine in haematology—Challenges and opportunities

“…Increasing possibilities to measure disease burden from other sites than the tumour, through, for example, measurement of ctDNA, is also likely to become a valuable tool to capture genetic aberrations more comprehensively [96,139]. This may especially be useful for diseases such as lymphomas, where recurrent analyses of tumour material may not readily be available [140,141]. In addition, in studies using ctDNA, specific genetic lesions have been identified in samples from the blood of patients with aggressive lymphoma that were not found in the original tumour, indicating both intratumour heterogeneity and clonal evolution [96].…”

Pan-cancer detection and typing by mining patterns in large genome-wide cell-free DNA sequencing datasets

“…Plasma was isolated via a standard, two-step centrifugation procedure and stored at -80°C. Previously published sequencing data from 260 healthy subjects (3) and 177 patients with Hodgkin’s lymphoma (13) were included in the study.…”