American Association for Cancer Research
bcd-22-0128_supplementary_figures_suppsf1-sf17.docx (9.03 MB)

Supplementary Figures from Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells

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journal contribution
posted on 2023-05-01, 08:40 authored by Francesco Maura, Bachisio Ziccheddu, Jenny Z. Xiang, Bhavneet Bhinder, Joel Rosiene, Federico Abascal, Kylee H. Maclachlan, Kenneth Wha Eng, Manik Uppal, Feng He, Wei Zhang, Qi Gao, Venkata D. Yellapantula, Vicenta Trujillo-Alonso, Sunita I. Park, Matthew J. Oberley, Elizabeth Ruckdeschel, Megan S. Lim, Gerald B. Wertheim, Matthew J. Barth, Terzah M. Horton, Andriy Derkach, Alexandra E. Kovach, Christopher J. Forlenza, Yanming Zhang, Ola Landgren, Craig H. Moskowitz, Ethel Cesarman, Marcin Imielinski, Olivier Elemento, Mikhail Roshal, Lisa Giulino-Roth

All supplementary figures S1-S17


National Cancer Institute (NCI)

United States Department of Health and Human Services

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Hartwell Foundation (The Hartwell Foundation)

The Children's Oncology Group

American Society of Hematology (ASH)

Gant Family Foundation

Riney Family Foundation



The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Using this approach, we now report the whole-genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events leading to cHL. We identified alterations in driver genes not previously described in cHL, APOBEC mutational activity, and the presence of complex structural variants including chromothripsis. We found that high ploidy in cHL is often acquired through multiple, independent chromosomal gains events including whole-genome duplication. Evolutionary timing analyses revealed that structural variants enriched for RAG motifs, driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID-driven mutagenesis usually preceded large chromosomal gains. This study provides a temporal reconstruction of cHL pathogenesis. Previous studies in cHL were limited to coding sequences and therefore not able to comprehensively decipher the tumor complexity. Here, leveraging cHL whole-genome characterization, we identify driver events and reconstruct the tumor evolution, finding that structural variants, driver mutations, and AID mutagenesis precede chromosomal gains.This article is highlighted in the In This Issue feature, p. 171

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