Molecular evolution of classic Hodgkin lymphoma revealed through whole-genome sequencing of Hodgkin and Reed Sternberg cells Journal Article

   

Authors:	Maura, F.; Ziccheddu, B.; Xiang, J. Z.; Bhinder, B.; Rosiene, J.; Abascal, F.; Maclachlan, K. H.; Eng, K. W.; Uppal, M.; He, F.; Zhang, W.; Gao, Q.; Yellapantula, V. D.; Trujillo-Alonso, V.; Park, S. I.; Oberley, M. J.; Ruckdeschel, E.; Lim, M. S.; Wertheim, G. B.; Barth, M. J.; Horton, T. M.; Derkach, A.; Kovach, A. E.; Forlenza, C. J.; Zhang, Y.; Landgren, O.; Moskowitz, C. H.; Cesarman, E.; Imielinski, M.; Elemento, O.; Roshal, M.; Giulino-Roth, L.
Article Title:	Molecular evolution of classic Hodgkin lymphoma revealed through whole-genome sequencing of Hodgkin and Reed Sternberg cells
Abstract:	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 identifi ed alterations in driver genes not previously described in cHL, APOBEC mutational activity, and the presence of complex struc-tural variants including chromothripsis. We found that high ploidy in cHL is often acquired through mul-tiple, 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.
Keywords:	mutations; expression; disease; recurrent; heterogeneity; sternberg cells; hodgkin; gene rearrangements; cancer; circulating tumor dna; cd30(+)
Journal Title:	Blood Cancer Discovery
Volume:	4
Issue:	3
ISSN:	2643-3230
Publisher:	American Association for Cancer Research
Date Published:	2023-05-01
Start Page:	208
End Page:	227
Language:	English
ACCESSION:	WOS:000986387900001
DOI:	10.1158/2643-3230.Bcd-22-0128
PROVIDER:	wos
PMCID:	PMC10150291
PUBMED:	36723991
Notes:	Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/206735