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Circulating cell-free DNA sheds light on genetic diversity of Hodgkin's lymphoma
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Massive parallel sequencing of circulating cell-free DNA in patients with nodular sclerosis Hodgkin’s lymphoma provided information about genomic imbalances in Hodgkin/Reed-Sternberg cells, according to study results.
These analyses may provide an opportunity for early response monitoring, as well as for the evaluation of potential biomarkers and targeted therapy, the researchers wrote.
“Clearly, the diagnosis of Hodgkin’s lymphoma remains a pathological diagnosis on a lymph node biopsy,” Peter Vandenberghe, MD, PhD, of the departments of human genetics and hematology at KU Leuven in Belgium, told HemOnc Today. “However, cell-free DNA is like a liquid biopsy of Hodgkin/Reed-Sternberg cells, and it allows us to interrogate the genome of the Hodgkin/Reed-Sternberg cells. This is more straightforward and convenient than laser-microdissection of Hodgkin/Reed-Sternberg cells from biopsies.”
Vandenberghe and colleagues were first prompted to investigate whether circulating cell-free DNA could inform researchers about the genetics of Hodgkin’s lymphoma due to findings from a non-invasive prenatal test in one woman who was pregnant. Researchers discovered genomic imbalances in the woman’s circulating cell-free DNA, and she subsequently was diagnosed with early-stage nodular sclerosis Hodgkin’s lymphoma during gestation.
The current analysis included an additional nine patients with biopsy-proven nodular sclerosis Hodgkin’s lymphoma. Of these patients, eight were at first diagnosis and one had relapsed disease. Seven patients had stage IIA disease and two had stage IVB disease.
An analysis of the circulating cell-free DNA demonstrated genomic imbalances in eight patients. Abnormalities that occurred in five or more patients included gains of chromosome 2p, 3q, 5p and 9p/9pter. Researchers also observed gains in 8q/8qter, chromosome 12 and chromosome 19 in four patients, and loss of 1p, 6q, 7q/7qter, 9qter, 10q, 11qter, 13q and 22q in at least four patients.
Researchers validated these results using fluorescence in-situ hybridization (FISH) of Hodgkin/Reed-Sternberg cells in biopsy samples. Results indicated only three discordances between the FISH and circulating cell-free DNA analyses.
“This cogently demonstrates that circulating cell-free DNA contains DNA derived from and representative of Hodgkin/Reed-Sternberg cells,” Vandenberghe and colleagues wrote.
Eight patients from the current analysis and the pregnant woman were treated with a combination of doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy. Three patients achieved complete metabolic remission.
Researchers did not observe the baseline genomic abnormalities in subsequent circulating cell-free DNA analyses performed between 15 and 43 days after treatment initiation. This difference suggests that circulating cell-free DNA can be monitored for early response, the researchers wrote.
“This finding opens exciting new prospects for exploring the genetic diversity of Hodgkin’s lymphoma upfront at diagnosis and for following disease response in a non-invasive fashion under therapy,” Vandenberghe said.
If validated in additional analyses, the monitoring of circulating cell-free DNA could help clinicians monitor patients for relapse, Stefan Hohaus, MD, of the Institute of Hematology at Catholic University of the Sacred Heart in Rome, Italy, wrote in an invited commentary.
“Normalization of the genomic imbalances in the cell-free DNA during treatment raises the hope that these changes could be used to assess response and monitor disease activity,” Hohaus wrote. “Sensitivity of the technique has to be determined, and careful clinical studies are needed to assess the diagnosis potential beyond the proof-of-principle of the work by Vandenberghe and colleagues … We can hope that such specific and sensitive blood tests might be applied as early markers of relapse, and reduce the need for repeated radiological examinations.”– by Alexandra Todak
Peter Vandenberghe, MD, PhD, can be reached at Center for Human Genetics, Herestraat 49, B-3000 Leuven, Belgium; email: peter.vandenberghe@uzleuven.be.
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