Aberrant transcriptome analysis of 3,760 hematologic malignancies reveals LRP1B as hairy cell leukemia variant biomarker
Aberrant transcriptome analysis of 3,760 hematologic malignancies reveals LRP1B as hairy cell leukemia variant biomarker
Abstract Rare driver mutations are suspected to substantially contribute to the large heterogeneity of hematologic malignancies, but their identification remains challenging. To address this issue, we generated the largest dataset to date of matched whole genome sequencing and total RNA sequencing of hematologic malignancies from 3,760 patients spanning 24 disease entities. To discover rare and large regulatory aberrations, we analyzed aberrant expression and splicing events using an extension of DROP (Detection of RNA Outliers Pipeline) and AbSplice, an algorithm that identifies genetic variants causing aberrant splicing. We found a median of seven aberrantly expressed genes, two aberrantly spliced genes, and two rare splice-affecting variants per sample. Each category showed significant enrichment for well-characterized driver genes, with odds ratios exceeding three among genes called in more than five samples. We next trained disease-specific driver gene prediction models integrating these data with recurrent mutation analyses. On held-out data, integrative modeling significantly outperformed modeling based solely on genomic data and revealed promising novel candidate driver genes. Moreover, we found a truncated form of the low density lipoprotein receptor LRP1B to be aberrantly overexpressed in about half of hairy cell leukemia variant (HCL-V) samples and, to a lesser extent, in closely related B-cell neoplasms. This observation, which was confirmed in an independent cohort, suggests LRP1B be a novel biomarker and a yet unreported functional role of LRP1B within these rare entities. Altogether, this dataset and the companion computational workflow constitute unique resources to deepen our understanding of rare oncogenic events in hematologic cancers.
Y¨|pez Vicente A.、Huber Sandra、Jadid Ahari Ata、Haferlach Torsten、Scheller Ines、Blombery Piers、Heinig Matthias、Wachutka Leonhard、Gagneur Julien、Secheyko Polina、Hutter Stephan、Wagner Nils、Traube Franziska R.、Oakes Christopher C.、Cao Xueqi、Seifert Marc
School of Computation Technical University of MunichM¨1nchner Leuk?mielabor GmbH (MLL)School of Computation Technical University of MunichM¨1nchner Leuk?mielabor GmbH (MLL)School of Computation Technical University of Munich||Computational Health Center, Helmholtz Center MunichPeter MacCallum Cancer Centre||University of Melbourne||Torsten Haferlach Leukaemiediagnostik StiftungSchool of Computation Technical University of Munich||Computational Health Center, Helmholtz Center MunichSchool of Computation Technical University of MunichSchool of Computation Technical University of Munich||Graduate School of Quantitative Biosciences (QBM)||Computational Health Center, Helmholtz Center Munich||Institute of Human Genetics, School of Medicine, Technical University of MunichSchool of Computation Technical University of Munich||Faculty of Biology, Ludwig-Maximilians-University MunichM¨1nchner Leuk?mielabor GmbH (MLL)School of Computation Technical University of Munich||Helmholtz Association - Munich School for Data Science (MUDS)School of Computation Technical University of Munich||Institute of Biochemistry and Technical Biochemistry, University of StuttgartDivision of Hematology, Department of Internal Medicine, The Ohio State UniversitySchool of Computation Technical University of Munich||Graduate School of Quantitative Biosciences (QBM)Department of Haematology, Oncology and Clinical Immunology, University Hospital D¨1sseldorf
医学研究方法基础医学肿瘤学
Y¨|pez Vicente A.,Huber Sandra,Jadid Ahari Ata,Haferlach Torsten,Scheller Ines,Blombery Piers,Heinig Matthias,Wachutka Leonhard,Gagneur Julien,Secheyko Polina,Hutter Stephan,Wagner Nils,Traube Franziska R.,Oakes Christopher C.,Cao Xueqi,Seifert Marc.Aberrant transcriptome analysis of 3,760 hematologic malignancies reveals LRP1B as hairy cell leukemia variant biomarker[EB/OL].(2025-03-28)[2025-04-24].https://www.medrxiv.org/content/10.1101/2023.08.08.23293420.点此复制
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