Blood cancer discovery · 2023
Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
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Maura Francesco, Ziccheddu Bachisio, Xiang Jenny Z, Bhinder Bhavneet, Rosiene Joel, Abascal Federico, Maclachlan Kylee H, Eng Kenneth Wha, Uppal Manik, He Feng, Zhang Wei, Gao Qi, Yellapantula Venkata D, Trujillo-Alonso Vicenta, Park Sunita I, Oberley Matthew J, Ruckdeschel Elizabeth, Lim Megan S, Wertheim Gerald B, Barth Matthew J, Horton Terzah M, Derkach Andriy, Kovach Alexandra E, Forlenza Christopher J, Zhang Yanming, Landgren Ola, Moskowitz Craig H, Cesarman Ethel, Imielinski Marcin, Elemento Olivier, Roshal Mikhail, Giulino-Roth Lisa
Аннотация
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.
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.