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Longitudinal genome-wide analysis of patients with chronic lymphocytic leukemia reveals complex evolution of clonal architecture at disease progression and at the time of relapse

Leukemia volume 26, pages 1698–1701 (2012)Cite this article

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Recent advances in comprehensive genomic analyses, which include array-based comparative genomic hybridization (aCGH) and massively parallel sequencing, have permitted a better appreciation of the genetic complexity and clonal heterogeneity of the human tumor cell population.1, 2, 3, 4, 5, 6, 7, 8 Although such analyses of tumor cells have provided evidence of extraordinary genomic complexity and intra-clonal genetic diversity in several cancers, little is known of the genetic architecture and intra-clonal heterogeneity of the leukemic clone in chronic lymphocytic leukemia (CLL) patients,9, 10, 11 and no sequential global genomic analyses have been performed to better understand the process of clonal evolution associated with the tumor cells in this malignancy. In order to gain insight into the genetic complexity and clonal evolution underlying disease progression/relapse, we performed a sequential, longitudinal analysis of tumor samples in 22 CLL patients.

All 22 patients had genome-wide genetic analysis performed by aCGH on at least two sequential tumor samples >6 months apart (54 samples from 22 patients with two to four time points (TPs) analyzed per patient). For the purposes of this study, we classified samples as; TP1 collected >6 months before starting first-line treatment: TP2 consisting of tumor samples at the time of progression requiring treatment and TP3 consisting of tumor samples collected >6 months after initial treatment but before subsequent treatments.12 In cases showing genetic changes between TPs, fluorescence in situ hybridization (FISH) analyses were performed. Demographics, TPs analyzed and the technical approach used in each case are summarized in Supplementary Material, Supplementary Table S2 and Figure S1.

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Acknowledgements

EB is a recipient of the Marriott Specialized Workforce Development Awards in Individualized Medicine. NEK is the recipient of the NIH awards CA95241 and CA111953. DFJ is the recipient of the NIH award CA136591.

AUTHOR CONTRIBUTIONS

EB, NK, TDS, RF and DFJ designed the study; EB, SVW, SS, JEP, DVD MB, TS and RCT performed the research; EB wrote the paper and all authors reviewed and gave final approval of the manuscript.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ, USA

    E Braggio & S VanWier

  2. Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA

    N E Kay, T Sassoon & T D Shanafelt

  3. Department of Immunology, Mayo Clinic, Rochester, MN, USA

    R C Tschumper & D F Jelinek

  4. Department of Laboratory Medicine and Pathology, Division of Laboratory Genetics, Mayo Clinic, Rochester, MN, USA

    S Smoley & D L Van Dyke

  5. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    J E Eckel-Passow

  6. Translational Genomics, Phoenix, AZ, USA

    M Barrett

  7. Department of Hematology, Ohio State University, Columbus, OH, USA

    J C Byrd

  8. Department of Hematology–Oncology, Mayo Clinic, Scottsdale, AZ, USA

    R Fonseca

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  1. E Braggio
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Corresponding author

Correspondence to R Fonseca.

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Competing interests

RF is a consultant for Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine and Lilly (all less than $10 000). RF receives research support from Cylene, Onyx and Celgene. The remaining authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Leukemia website

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Braggio, E., Kay, N., VanWier, S. et al. Longitudinal genome-wide analysis of patients with chronic lymphocytic leukemia reveals complex evolution of clonal architecture at disease progression and at the time of relapse. Leukemia 26, 1698–1701 (2012). https://doi.org/10.1038/leu.2012.14

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