Integrated Genomic and Transcriptomic Analysis Improves Disease Classification and Risk Stratification of MDS with Ring Sideroblasts
Journal article, 2023
Purpose: Ring sideroblasts (RS) define the low-risk myelodysplastic neoplasm (MDS) subgroup with RS but may also reflect erythroid dysplasia in higher risk myeloid neoplasm. The benign behavior of MDS with RS (MDSRSþ) is limited to SF3B1-mutated cases without additional high-risk genetic events, but one third of MDSRSþ carry no SF3B1 mutation, suggesting that different molecular mechanisms may underlie RS formation. We integrated genomic and transcriptomic analyses to evaluate whether transcriptome profiles may improve current risk stratification. Experimental Design: We studied a prospective cohort of MDSRSþ patients irrespective of World Health Organization (WHO) class with regard to somatic mutations, copy-number alterations, and bone marrow CD34þ cell transcriptomes to assess whether transcriptome profiles add to prognostication and provide input on disease classification. Results: SF3B1, SRSF2, or TP53 multihit mutations were found in 89% of MDSRSþ cases, and each mutation category was associated with distinct clinical outcome, gene expression, and alternative splicing profiles. Unsupervised clustering analysis identified three clusters with distinct hemopoietic stem and progenitor (HSPC) composition, which only partially overlapped with mutation groups. IPSS-M and the transcriptome-defined proportion of megakaryocyte/erythroid progenitors (MEP) independently predicted survival in multivariable analysis. Conclusions: These results provide essential input on the molecular basis of SF3B1-unmutated MDSRSþ and propose HSPC quantification as a prognostic marker in myeloid neoplasms with RS.
Author
Gabriele Todisco
Karolinska Institutet
Fondazione IRCCS Policlinico San Matteo
Universita degli studi di Pavia
Maria Creignou
Karolinska University Hospital
Karolinska Institutet
Elsa Bernard
Memorial Sloan-Kettering Cancer Center
Ann Charlotte Björklund
Karolinska Institutet
Pedro Luis Moura
Karolinska Institutet
Bianca Tesi
Karolinska University Hospital
Karolinska Institutet
Teresa Mortera-Blanco
Karolinska Institutet
Birgitta Sander
Karolinska University Hospital
Monika Jansson
Karolinska Institutet
Karolinska University Hospital
Gunilla Walldin
Karolinska Institutet
Karolinska University Hospital
Indira Barbosa
Karolinska Institutet
Susanne Reinsbach
Chalmers, Life Sciences, Systems and Synthetic Biology
Isabel Juliana Hofman
Karolinska Institutet
Christer Nilsson
Karolinska University Hospital
Karolinska Institutet
Tetsuichi Yoshizato
Karolinska Institutet
Marios Dimitriou
Karolinska Institutet
David Chang
Karolinska Institutet
Svannildur Olafsdottir
Karolinska Institutet
Sigita Venckute Larsson
Karolinska Institutet
Magnus Tobiasson
Karolinska University Hospital
Karolinska Institutet
Luca Malcovati
Fondazione IRCCS Policlinico San Matteo
Universita degli studi di Pavia
Petter Woll
Karolinska Institutet
Sten Eirik W. Jacobsen
Karolinska Institutet
Weatherall Institute of Molecular Medicine
Elli Papaemmanuil
Memorial Sloan-Kettering Cancer Center
Eva Hellström-Lindberg
Karolinska University Hospital
Karolinska Institutet
Clinical Cancer Research
1078-0432 (ISSN) 15573265 (eISSN)
Vol. 29 20 4256-4267Subject Categories (SSIF 2011)
Hematology
Cancer and Oncology
DOI
10.1158/1078-0432.CCR-23-0538
PubMed
37498312