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 inHaematologica (Roma) Vol. 108; no. 10; pp. 2664 - 2676
Main Authors Lütge, Almut, Lu, Junyan, Hüllein, Jennifer, Walther, Tatjana, Sellner, Leopold, Wu, Bian, Rosenquist, Richard, Oakes, Christopher C, Dietrich, Sascha, Huber, Wolfgang, Zenz, Thorsten
Format Journal Article
LanguageEnglish
Published Italy Fondazione Ferrata Storti 01.10.2023
Ferrata Storti Foundation
Subjects
Chronic Lymphocytic Leukemia
Medicin och hälsovetenskap
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Abstract 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.
AbstractList 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 non-additive 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.
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.
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 non-additive 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.
Author Wu, Bian
Huber, Wolfgang
Walther, Tatjana
Sellner, Leopold
Zenz, Thorsten
Dietrich, Sascha
Lu, Junyan
Rosenquist, Richard
Lütge, Almut
Oakes, Christopher C
Hüllein, Jennifer
AuthorAffiliation 9 Clinical Genetics, Karolinska University Hospital , Solna, Sweden
3 SIB Swiss Institute of Bioinformatics, University of Zurich , Zurich, Switzerland
8 Department of Molecular Medicine and Surgery, Karolinska Institutet , Stockholm, Sweden
4 Medical Faculty Heidelberg, Heidelberg University , Heidelberg, Germany
2 Department of Molecular Life Sciences, University of Zurich , Zurich, Switzerland
7 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
1 Genome Biology Unit , EMBL, Heidelberg, Germany
11 Department of Medical Oncology and Hematology, University Hospital Zurich , Zurich, Switzerland
5 Molecular Therapy in Hematology and Oncology & Department of Translational Oncology, NCT and DKFZ, Heidelberg, Germany
6 Department of Medicine V, Heidelberg University Hospital , Heidelberg, Germany
10 Department of Internal Medicine, Division of Hematology, The Ohio State University , Columbus, OH, USA
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  givenname: Bian
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  fullname: Wu, Bian
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  email: wolfgang.huber@embl.org
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  givenname: Thorsten
  surname: Zenz
  fullname: Zenz, Thorsten
  email: thorsten.zenz@usz.ch
  organization: Molecular Therapy in Hematology and Oncology and Department of Translational Oncology, NCT and DKFZ, Heidelberg, Germany; Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich. thorsten.zenz@usz.ch
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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.
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Snippet Understanding the molecular and phenotypic heterogeneity of cancer is a prerequisite for effective treatment. For chronic lymphocytic leukemia (CLL), recurrent...
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Title Subgroup-specific gene expression profiles and mixed epistasis in chronic lymphocytic leukemia
URI https://www.ncbi.nlm.nih.gov/pubmed/37226709
https://search.proquest.com/docview/2819276192
https://pubmed.ncbi.nlm.nih.gov/PMC10614035
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http://kipublications.ki.se/Default.aspx?queryparsed=id:237226709
https://doaj.org/article/537cbfcc61214f46a68b7f5307b978b4
Volume 108
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