Figure 1

Longitudinal analysis of SVs of case 016 over a period of 11 years of disease evolution. (a) A 59-year-old male was diagnosed with CLL, IGHV unmutated subtype at stage A0 in 1996. He did not require treatment until 2002, when CLL progressed to stage BII, because of the development of massive lymph nodes, splenomegaly and constitutional symptoms. He received fludarabine-cyclophosphamide-mitoxantrone (six cycles), with complete response and negative detection of minimal residual disease (MRD). In 2006, the patient relapsed (BII), and was retreated with six cycles of fludarabine-cyclophosphamide-mitoxantrone-rituximab, obtaining a complete response, MRD negative. He was free of disease in 2009 when normal mononuclear cells were collected. After a second relapse (BI) in 2011 with an axillar bulky lymphadenopathy, the patient received six cycles of rituximab-bendamustine, with excellent response, MRD negative, which is maintained until December 2012. Somatic SV characterization was done by WGS of samples 016-T02 and 016-N09 (Supplementary Table S2). Mosaicism analysis of CNAs of sample 016-T02 was done by Illumina HumanOmni1-Quad array (Illumina, Inc., San Diego, CA, USA). Somatic point mutations analysis of sample 016-T02 was performed as described by exome sequencing⁷ and using an additional in-house pipeline. Validation of somatic SVs and point mutations in all samples was done by a targeted re-sequencing approach (Agilent SureSelect Target Enrichment; Agilent Technologies, Santa Clara, CA, USA) and by Affymetrix 6.0 SNP array (Affymetrix 6.0; Affymetrix, Santa Clara, CA, USA). Detection of fusion transcripts of RNA in sample 016-T02 were performed by RNA sequencing.⁷ Further detailed information is provided in Supplementary Methods. (b) Circos representing the SVs detected in sample 016-T02, before starting treatment, in consistence with the chromothripsis pattern. (c) Circos representing the SVs detected in pre-treatment (016-T00) and post-treatment (016-T05 and 016-T11) samples. (d) Evolution of cancer cell CF over time for SNVs and chromothripsis rearrangements. Smoothed solid curves represent the average profile of the time evolution of cancer cell percentages of the mutations detected in all time points (black) and only in sample 016-T02 (red).