Title | Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Maura F, Ziccheddu B, Xiang JZ, Bhinder B, Rosiene J, Abascal F, Maclachlan KH, Eng KWha, Uppal M, He F, Zhang W, Gao Q, Yellapantula VD, Trujillo-Alonso V, Park SI, Oberley MJ, Ruckdeschel E, Lim MS, Wertheim GB, Barth MJ, Horton TM, Derkach A, Kovach AE, Forlenza CJ, Zhang Y, Landgren O, Moskowitz CH, Cesarman E, Imielinski M, Elemento O, Roshal M, Giulino-Roth L |
Journal | Blood Cancer Discov |
Volume | 4 |
Issue | 3 |
Pagination | 208-227 |
Date Published | 2023 May 01 |
ISSN | 2643-3249 |
Keywords | Evolution, Molecular, Flow Cytometry, Hodgkin Disease, Humans, Reed-Sternberg Cells |
Abstract | UNLABELLED: 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. SIGNIFICANCE: 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. |
DOI | 10.1158/2643-3230.BCD-22-0128 |
Alternate Journal | Blood Cancer Discov |
PubMed ID | 36723991 |
PubMed Central ID | PMC10150291 |
Grant List | K08 CA219473 / CA / NCI NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States P30 CA240139 / CA / NCI NIH HHS / United States |
Related Faculty:
Ethel Cesarman, M.D., Ph.D.