Peter Vandenberghe1, Iwona Wlodarska2, Thomas Tousseyn3, Luc Dehaspe2, Daan Dierickx4, Magali Verheecke5, Anne Uyttebroeck6, Oliver Bechter7, Michel Delforge4, Vincent Vandecaveye8, Nathalie Brison2, Gregor E G Verhoef4, Eric Legius2, Frederic Amant5, Joris R Vermeesch2. 1. Department of Human Genetics, Center for Human Genetics, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium; Department of Haematology, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium. Electronic address: peter.vandenberghe@uzleuven.be. 2. Department of Human Genetics, Center for Human Genetics, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium. 3. Department of Pathology, Translational Cell and Tissue Research, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium. 4. Department of Haematology, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium. 5. Department of Obstetrics and Gynaecology, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium. 6. Department of Paediatrics, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium. 7. Department of General Medical Oncology, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium. 8. Department of Radiology, KU Leuven - University of Leuven, University Hospitals Leuven, Leuven, Belgium.
Abstract
BACKGROUND: Hodgkin's lymphoma is one of the most common lymphoid neoplasms in young adults, but the low abundance of neoplastic Hodgkin/Reed-Sternberg cells in the tumour hampers the elucidation of its pathogenesis, biology, and diversity. After an incidental observation that genomic aberrations known to occur in Hodgkin's lymphoma were detectable in circulating cell-free DNA, this study was undertaken to investigate whether circulating cell-free DNA can be informative about genomic imbalances in Hodgkin's lymphoma. METHODS: We applied massive parallel sequencing to circulating cell-free DNA in a prospective study of patients with biopsy proven nodular sclerosis Hodgkin's lymphoma. Genomic imbalances in Hodgkin/Reed-Sternberg cells were investigated by fluorescence in-situ hybridisation (FISH) on tumour specimens. FINDINGS: By non-invasive prenatal testing, we observed several genomic imbalances in circulating cell-free DNA of a pregnant woman, who was subsequently diagnosed with early-stage nodular sclerosis Hodgkin's lymphoma stage IIA during gestation. FISH on tumour tissue confirmed corresponding genomic imbalances in Hodgkin/Reed-Sternberg cells. We prospectively studied circulating cell-free DNA of nine nodular sclerosis Hodgkin's lymphoma cases: eight at first diagnosis and one at first relapse. Seven patients had stage IIA disease and two had stage IVB disease. In eight, genomic imbalances were detected, including, among others, gain of chromosomes 2p and 9p, known to occur in Hodgkin's lymphoma. These gains and losses in circulating cell-free DNA were extensively validated by FISH on Hodgkin/Reed-Sternberg cells in biopsy samples. Initiation of chemotherapy induced normalisation of circulating cell-free DNA profiles within 2-6 weeks. The cell cycle indicator Ki67 and cleaved caspase-3 were detected in Hodgkin/Reed-Sternberg cells by immunohistochemistry, suggesting high turnover of Hodgkin/Reed-Sternberg cells. INTERPRETATION: In early and advanced stage nodular sclerosis Hodgkin's lymphoma, genomic imbalances in Hodgkin/Reed-Sternberg cells can be identified by massive parallel sequencing of circulating cell-free DNA at diagnosis. The rapid normalisation of circulating cell-free DNA profiles on therapy initiation suggests a potential role for circulating cell-free DNA profiling in early response monitoring. This finding creates several new possibilities for exploring the diversity of Hodgkin's lymphoma, and has potential implications for the future clinical development of biomarkers and precision therapy for this malignancy. FUNDING: KU Leuven-University of Leuven and University Hospitals Leuven.
BACKGROUND:Hodgkin's lymphoma is one of the most common lymphoid neoplasms in young adults, but the low abundance of neoplastic Hodgkin/Reed-Sternberg cells in the tumour hampers the elucidation of its pathogenesis, biology, and diversity. After an incidental observation that genomic aberrations known to occur in Hodgkin's lymphoma were detectable in circulating cell-free DNA, this study was undertaken to investigate whether circulating cell-free DNA can be informative about genomic imbalances in Hodgkin's lymphoma. METHODS: We applied massive parallel sequencing to circulating cell-free DNA in a prospective study of patients with biopsy proven nodular sclerosis Hodgkin's lymphoma. Genomic imbalances in Hodgkin/Reed-Sternberg cells were investigated by fluorescence in-situ hybridisation (FISH) on tumour specimens. FINDINGS: By non-invasive prenatal testing, we observed several genomic imbalances in circulating cell-free DNA of a pregnant woman, who was subsequently diagnosed with early-stage nodular sclerosis Hodgkin's lymphoma stage IIA during gestation. FISH on tumour tissue confirmed corresponding genomic imbalances in Hodgkin/Reed-Sternberg cells. We prospectively studied circulating cell-free DNA of nine nodular sclerosis Hodgkin's lymphoma cases: eight at first diagnosis and one at first relapse. Seven patients had stage IIA disease and two had stage IVB disease. In eight, genomic imbalances were detected, including, among others, gain of chromosomes 2p and 9p, known to occur in Hodgkin's lymphoma. These gains and losses in circulating cell-free DNA were extensively validated by FISH on Hodgkin/Reed-Sternberg cells in biopsy samples. Initiation of chemotherapy induced normalisation of circulating cell-free DNA profiles within 2-6 weeks. The cell cycle indicator Ki67 and cleaved caspase-3 were detected in Hodgkin/Reed-Sternberg cells by immunohistochemistry, suggesting high turnover of Hodgkin/Reed-Sternberg cells. INTERPRETATION: In early and advanced stage nodular sclerosis Hodgkin's lymphoma, genomic imbalances in Hodgkin/Reed-Sternberg cells can be identified by massive parallel sequencing of circulating cell-free DNA at diagnosis. The rapid normalisation of circulating cell-free DNA profiles on therapy initiation suggests a potential role for circulating cell-free DNA profiling in early response monitoring. This finding creates several new possibilities for exploring the diversity of Hodgkin's lymphoma, and has potential implications for the future clinical development of biomarkers and precision therapy for this malignancy. FUNDING: KU Leuven-University of Leuven and University Hospitals Leuven.
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