Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma

Blood. 2018 May 31;131(22):2413-2425. doi: 10.1182/blood-2017-11-812073. Epub 2018 Feb 15.


The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep next-generation sequencing approach for circulating tumor DNA (ctDNA), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying STAT6 as the most frequently mutated gene in ∼40% of cases, we refined the current knowledge of cHL genetics. Longitudinal ctDNA profiling identified treatment-dependent patterns of clonal evolution in patients relapsing after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free tool to track residual disease that may integrate positron emission tomography imaging for the early identification of chemorefractory patients with cHL. Collectively, our results provide the proof of concept that ctDNA may serve as a novel precision medicine biomarker in cHL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Bleomycin / administration & dosage
  • Bleomycin / therapeutic use
  • Circulating Tumor DNA / blood
  • Circulating Tumor DNA / genetics*
  • Clonal Evolution / drug effects
  • Dacarbazine / administration & dosage
  • Dacarbazine / therapeutic use
  • Doxorubicin / administration & dosage
  • Doxorubicin / therapeutic use
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Hodgkin Disease / blood
  • Hodgkin Disease / drug therapy
  • Hodgkin Disease / genetics*
  • Hodgkin Disease / pathology
  • Humans
  • Immunotherapy
  • Mutation / drug effects
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm, Residual / blood
  • Neoplasm, Residual / drug therapy
  • Neoplasm, Residual / genetics*
  • Reed-Sternberg Cells / drug effects
  • Reed-Sternberg Cells / metabolism
  • Reed-Sternberg Cells / pathology
  • STAT6 Transcription Factor / genetics
  • Tumor Cells, Cultured
  • Vinblastine / administration & dosage
  • Vinblastine / therapeutic use


  • Antineoplastic Agents
  • Circulating Tumor DNA
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Bleomycin
  • Vinblastine
  • Dacarbazine
  • Doxorubicin