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

Valeria Spina, Alessio Bruscaggin, Annarosa Cuccaro, Maurizio Martini, Martina Di Trani, Gabriela Forestieri, Martina Manzoni, Adalgisa Condoluci, Alberto Arribas, Lodovico Terzi-Di-Bergamo, Silvia Laura Locatelli, Elisa Cupelli, Luca Ceriani, Alden A. Moccia, Anastasios Stathis, Luca Nassi, Clara Deambrogi, Fary Diop, Francesca Guidetti, Alessandra Cocomazzi & 17 others Salvatore Annunziata, Vittoria Rufini, Alessandro Giordano, Antonino Neri, Renzo Boldorini, Bernhard Gerber, Francesco Bertoni, Michele Ghielmini, Georg Stüssi, Armando Santoro, Franco Cavalli, Emanuele Zucca, Luigi Maria Larocca, Gianluca Gaidano, Stefan Hohaus, Carmelo Carlo-Stella, Davide Rossi

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2413-2425
Number of pages13
JournalBlood
Volume131
Issue number22
DOIs
Publication statusPublished - May 31 2018

Fingerprint

Clonal Evolution
Molecular Evolution
Hodgkin Disease
Tumors
DNA
Chemotherapy
Neoplasms
Drug Therapy
Immunotherapy
Reed-Sternberg Cells
Dacarbazine
Precision Medicine
Positron emission tomography
DNA Fingerprinting
Vinblastine
Genetics
Biopsy
Bleomycin
Biomarkers
Positron-Emission Tomography

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Spina, V., Bruscaggin, A., Cuccaro, A., Martini, M., Trani, M. D., Forestieri, G., ... Rossi, D. (2018). Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood, 131(22), 2413-2425. https://doi.org/10.1182/blood-2017-11-812073

Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. / Spina, Valeria; Bruscaggin, Alessio; Cuccaro, Annarosa; Martini, Maurizio; Trani, Martina Di; Forestieri, Gabriela; Manzoni, Martina; Condoluci, Adalgisa; Arribas, Alberto; Terzi-Di-Bergamo, Lodovico; Locatelli, Silvia Laura; Cupelli, Elisa; Ceriani, Luca; Moccia, Alden A.; Stathis, Anastasios; Nassi, Luca; Deambrogi, Clara; Diop, Fary; Guidetti, Francesca; Cocomazzi, Alessandra; Annunziata, Salvatore; Rufini, Vittoria; Giordano, Alessandro; Neri, Antonino; Boldorini, Renzo; Gerber, Bernhard; Bertoni, Francesco; Ghielmini, Michele; Stüssi, Georg; Santoro, Armando; Cavalli, Franco; Zucca, Emanuele; Larocca, Luigi Maria; Gaidano, Gianluca; Hohaus, Stefan; Carlo-Stella, Carmelo; Rossi, Davide.

In: Blood, Vol. 131, No. 22, 31.05.2018, p. 2413-2425.

Research output: Contribution to journalArticle

Spina, V, Bruscaggin, A, Cuccaro, A, Martini, M, Trani, MD, Forestieri, G, Manzoni, M, Condoluci, A, Arribas, A, Terzi-Di-Bergamo, L, Locatelli, SL, Cupelli, E, Ceriani, L, Moccia, AA, Stathis, A, Nassi, L, Deambrogi, C, Diop, F, Guidetti, F, Cocomazzi, A, Annunziata, S, Rufini, V, Giordano, A, Neri, A, Boldorini, R, Gerber, B, Bertoni, F, Ghielmini, M, Stüssi, G, Santoro, A, Cavalli, F, Zucca, E, Larocca, LM, Gaidano, G, Hohaus, S, Carlo-Stella, C & Rossi, D 2018, 'Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma', Blood, vol. 131, no. 22, pp. 2413-2425. https://doi.org/10.1182/blood-2017-11-812073
Spina, Valeria ; Bruscaggin, Alessio ; Cuccaro, Annarosa ; Martini, Maurizio ; Trani, Martina Di ; Forestieri, Gabriela ; Manzoni, Martina ; Condoluci, Adalgisa ; Arribas, Alberto ; Terzi-Di-Bergamo, Lodovico ; Locatelli, Silvia Laura ; Cupelli, Elisa ; Ceriani, Luca ; Moccia, Alden A. ; Stathis, Anastasios ; Nassi, Luca ; Deambrogi, Clara ; Diop, Fary ; Guidetti, Francesca ; Cocomazzi, Alessandra ; Annunziata, Salvatore ; Rufini, Vittoria ; Giordano, Alessandro ; Neri, Antonino ; Boldorini, Renzo ; Gerber, Bernhard ; Bertoni, Francesco ; Ghielmini, Michele ; Stüssi, Georg ; Santoro, Armando ; Cavalli, Franco ; Zucca, Emanuele ; Larocca, Luigi Maria ; Gaidano, Gianluca ; Hohaus, Stefan ; Carlo-Stella, Carmelo ; Rossi, Davide. / Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. In: Blood. 2018 ; Vol. 131, No. 22. pp. 2413-2425.
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abstract = "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.",
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AU - Spina, Valeria

AU - Bruscaggin, Alessio

AU - Cuccaro, Annarosa

AU - Martini, Maurizio

AU - Trani, Martina Di

AU - Forestieri, Gabriela

AU - Manzoni, Martina

AU - Condoluci, Adalgisa

AU - Arribas, Alberto

AU - Terzi-Di-Bergamo, Lodovico

AU - Locatelli, Silvia Laura

AU - Cupelli, Elisa

AU - Ceriani, Luca

AU - Moccia, Alden A.

AU - Stathis, Anastasios

AU - Nassi, Luca

AU - Deambrogi, Clara

AU - Diop, Fary

AU - Guidetti, Francesca

AU - Cocomazzi, Alessandra

AU - Annunziata, Salvatore

AU - Rufini, Vittoria

AU - Giordano, Alessandro

AU - Neri, Antonino

AU - Boldorini, Renzo

AU - Gerber, Bernhard

AU - Bertoni, Francesco

AU - Ghielmini, Michele

AU - Stüssi, Georg

AU - Santoro, Armando

AU - Cavalli, Franco

AU - Zucca, Emanuele

AU - Larocca, Luigi Maria

AU - Gaidano, Gianluca

AU - Hohaus, Stefan

AU - Carlo-Stella, Carmelo

AU - Rossi, Davide

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