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Lymphoma

Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma

Leukemia volume 28, pages 1103–1112 (2014)Cite this article

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Abstract

Follicular lymphoma (FL) is characterized besides the t(14;18)(q32;q21), by recurrent chromosomal alterations and somatic mutations. In this study, we analyzed cases of FL in situ (FLIS) without manifest FL (mFL), partial involvement by FL (PFL) and paired cases of FLIS and mFL to detect possible early chromosomal imbalances, mutations, as well as DNA-methylation patterns of genomic regions of selected genes. We demonstrate that all paired FLIS and mFL cases were clonally related, based on IGH rearrangement patterns and BCL2 breakpoint sequences. FLIS and PFL had no or few secondary chromosomal imbalances detectable by array comparative genomic hybridization (FLIS 0.8 copy number alterations (CNA)/case; PFL 2.0 CNA/case; mFL 6.3 CNA/case) and a lower level of DNA methylation of genes recurrently de novo methylated in lymphomas, as compared with mFL. EZH2 Tyr641 mutations were detected in a subset of both FLIS (2/9) and PFL (1/3) cases. In conclusion, these findings provide evidence that FLIS represents a FL precursor lesion of long-lived clonal B cells carrying the t(14;18) with no or few secondary genetic changes. Our data suggest that there may be more than one distinct lesion driving the progression from FLIS to manifest lymphoma.

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Acknowledgements

We thank Dorit Schuster, Reina Zühlke-Jenisch, Magret Ratjen, Claudia Kloss, Anne Marie Adam and Sema Colak for their excellent technical assistance. IS was supported by a fellowship from the Alexander von Humboldt Foundation. This project is supported by the BMBF HämatoSys network project (FKZ0315452B; RS) and SFB 685 (LQ-M and FF).

Author contributions

LQ-M and RS designed the study, supervised the experimental work, analyzed data and wrote the manuscript. FF designed the study, analyzed data and helped writing the manuscript. JS, IS, AH performed the experimental work and helped writing the manuscript. IB performed and supervised the experimental work. MAP, SM-M and PA provided samples and clinical information.

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Author notes

  1. J Schmidt, I Salaverria and A Haake: These authors contributed equally to this study.

  2. R Siebert and L Quintanilla-Martinez: These authors contributed equally to this study.

Authors and Affiliations

  1. Institute of Pathology and Comprehensive Cancer Center, Eberhard-Karls-University of Tübingen, Tübingen, Germany

    J Schmidt, I Bonzheim, P Adam, F Fend & L Quintanilla-Martinez

  2. Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University, Kiel, Germany

    I Salaverria, A Haake & R Siebert

  3. Department of Pathology, Hospital Universitario Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, Santander, Spain

    S Montes-Moreno & M A Piris

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Correspondence to L Quintanilla-Martinez.

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Schmidt, J., Salaverria, I., Haake, A. et al. Increasing genomic and epigenomic complexity in the clonal evolution from in situ to manifest t(14;18)-positive follicular lymphoma. Leukemia 28, 1103–1112 (2014). https://doi.org/10.1038/leu.2013.307

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