Cancer development is a dynamic process during which the successive accumulation of mutations results in cells with increasingly malignant characteristics. Here, we show the clonal evolution pattern in myelodysplastic syndrome (MDS) patients receiving supportive care, with or without lenalidomide (follow-up 2.5-11 years). Whole-exome and targeted deep sequencing at multiple time points during the disease course reveals that both linear and branched evolutionary patterns occur with and without disease-modifying treatment. The application of disease-modifying therapy may create an evolutionary bottleneck after which more complex MDS, but also unrelated clones of haematopoietic cells, may emerge. In addition, subclones that acquired an additional mutation associated with treatment resistance (TP53) or disease progression (NRAS, KRAS) may be detected months before clinical changes become apparent. Monitoring the genetic landscape during the disease may help to guide treatment decisions.

Department of Haematology Centro Hospitalar de São João and Faculdade de Medicina da Universidade do Porto Alameda Professor Hernâni Monteiro Porto 4200 319 Portugal

Department of Hematology Radboud University Medical Center Geert Grooteplein Zuid 8 6525 GA Nijmegen The Netherlands

Department of Hematology University Medical Centre Groningen PO Box 30001 9700 RB Groningen The Netherlands

Department of Human Genetics Radboud University Medical Center Geert Grooteplein Zuid 8 6525 GA Nijmegen The Netherlands

Department of Pathology and Tumor Biology Graduate School of Medicine Kyoto University Yoshida Konoe cho Sakyo ku Kyoto shi Kyoto 606 8501 Japan

Department of Tumor Immunology Radboud University Medical Center Radboud Institute for Molecular Life Sciences Geert Grooteplein Zuid 8 6525 GA Nijmegen The Netherlands

Human Genome Center Institute of Medical Science The University of Tokyo 4 6 1 Shirokanedai Minato ku Tokyo 108 8639 Japan

Institute of Hematology and Blood Transfusion U Nemocnice 1 128 20 Prague 2 Czech Republic

Institute of Medical Informatics University of Münster Albert Schweitzer Campus 1 48149 Münster Germany

Laboratory of Hematology Radboud University Medical Center Geert Grooteplein Zuid 8 6525 GA Nijmegen The Netherlands

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