Subgroup-specific gene expression profiles and mixed epistasis in chronic lymphocytic leukemia
Understanding the molecular and phenotypic heterogeneity of cancer is a prerequisite for effective treatment. For chronic lymphocytic leukemia (CLL), recurrent genetic driver events have been extensively cataloged, but this does not suffice to explain the disease's diverse course. Here, we perf...
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| Published in | Haematologica (Roma) Vol. 108; no. 10; pp. 2664 - 2676 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Italy
Fondazione Ferrata Storti
01.10.2023
Ferrata Storti Foundation |
| Subjects | |
| Online Access | Get full text |
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| Summary: | Understanding the molecular and phenotypic heterogeneity of cancer is a prerequisite for effective treatment. For chronic lymphocytic leukemia (CLL), recurrent genetic driver events have been extensively cataloged, but this does not suffice to explain the disease's diverse course. Here, we performed RNA-sequencing on 184 CLL patient samples. Unsupervised analysis revealed two major, orthogonal axes of gene expression variation: the first one represented the mutational status of the immunoglobulin heavy variable (IGHV) genes, and concomitantly, the three-group stratification of CLL by global DNA methylation. The second axis aligned with trisomy 12 status and affected chemokine, MAPK and mTOR signaling. We discovered nonadditive effects (epistasis) of IGHV mutation status and trisomy 12 on multiple phenotypes, including the expression of 893 genes. Multiple types of epistasis were observed, including synergy, buffering, suppression and inversion, suggesting that molecular understanding of disease heterogeneity requires studying such genetic events not only individually but in combination. We detected strong differentially expressed gene signatures associated with major gene mutations and copy-number aberrations including SF3B1, BRAF and TP53, as well as del(17)(p13), del(13)(q14) and del(11)(q22.3) beyond dosage effect. Our study reveals previously underappreciated gene expression signatures for the major molecular subtypes in CLL and the presence of epistasis between them. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 RNA-sequencing data are available at European GenomephenomeArchive (EGA) under accession number EGAS00001001746. All code to reproduce this analysis is available at https://github.com/almutlue/transcriptome_cll(DOI:10.5281/zenodo.4600322). Analysis code and outputs are deployed as a browsable workflowr site: https://almutlue.github.io/transcriptome_cll/index.html (see also: Blischak JD, Carbonetto P, Stephens M. Creating and sharing reproducible research code the workflowr way. F1000Res. 2019;81749). Disclosures RR has received honoraria from Abbvie, AstraZeneca, Janssen, Illumina and Roche. LS is currently an employee of Takeda. TZ has received honoraria from Abbvie, AstraZeneca, Janssen, Beigene, Gilead, Novartis, Janpix and Roche. The remaining authors have no conflicts of interest to disclose. AL developed the concept, collected and analyzed data, perfomed formal data analysis, visualized the project, developed the methodology, wrote the original draft, and reviewed and edited the manuscript. JL developed the concept, performed formal analysis, developed the methodology, wrote the original draft, reviewed and edited the manuscript. JH and TW collected and analyzed data. LS, BW, CO and SD collected and analyzed data, reviewed and edited the manuscript. RR collected and analyzed data; wrote, reviewed and edited the manuscript. WH and TZ developed the concept and the methology, supervised the project, performed project management, wrote the original draft, and reviewed and edited the manuscript. Contributions Data-sharing statement |
| ISSN: | 0390-6078 1592-8721 1592-8721 |
| DOI: | 10.3324/haematol.2022.281869 |