Published online 18 July 2008
Haematologica, Vol 93, Issue 9, 1318-1326 doi:10.3324/haematol.12875
Copyright © 2008 by Ferrata Storti Foundation

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Malignant Lymphomas

Detection of genomic imbalances in microdissected Hodgkin and Reed-Sternberg cells of classical Hodgkin’s lymphoma by array-based comparative genomic hybridization

Sylvia Hartmann¹, José I. Martin-Subero², Stefan Gesk², Julia Hüsken¹, Maciej Giefing^2,3, Inga Nagel², Jennifer Riemke², Andreas Chott⁴, Wolfram Klapper⁵, Marie Parrens⁶, Jean-Philippe Merlio⁶, Ralf Küppers⁷, Andreas Bräuninger¹, Reiner Siebert², Martin-Leo Hansmann¹

¹ Senckenberg Institute of Pathology, University of Frankfurt, Frankfurt, Germany
² Institute of Human Genetics, Christian-Albrechts-University Kiel, University Hospital Schleswig- Holstein, Campus Kiel, Kiel, Germany
³ Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
⁴ Dept. of Pathology, Medical University of Vienna, Vienna, Austria
⁵ Dept. of Pathology, Christian-Albrechts-University Kiel, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
⁶ Dept. of Pathology and Molecular Biology, CHU and University of Bordeaux 2, Bordeaux, France
⁷ Institute for Cell Biology (Tumor Research), University of Duisburg-Essen, Medical School, Essen, Germany

Correspondence: Sylvia Hartmann, Senckenberg Institute of Pathology, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail:s.hartmann{at}em.uni-frankfurt.de

Background: Cytogenetic analysis of classical Hodgkin’s lymphoma is limited by the low content of the neoplastic Hodgkin-Reed-Sternberg cells in the affected tissues. However, available cytogenetic data point to an extreme karyotype complexity. To obtain insights into chromosomal imbalances in classical Hodgkin’s lymphoma, we applied array-based comparative genomic hybridization (array comparative genomic hybridization) using DNA from microdissected Hodgkin-Reed-Sternberg cells.

Design and Methods: To avoid biases introduced by DNA amplification for array comparative genomic hybridization, cHL cases rich in Hodgkin-Reed-Sternberg cells were selected. DNA obtained from approximately 100,000 microdissected Hodgkin-Reed-Sternberg cells of each of ten classical Hodgkin’s lymphoma cases was hybridized onto commercial 105 K oligonucleotide comparative genomic hybridization microarrays. Selected imbalances were confirmed by interphase cytogenetics and quantitative polymerase chain reaction analysis and further studied in an independent series of classical Hodgkin’s lymphoma.

Results: Gains identified in at least five cHL affected 2p12-16, 5q15-23, 6p22, 8q13, 8q24, 9p21-24, 9q34, 12q13-14, 17q12, 19p13, 19q13 and 20q11 whereas losses recurrent in at least five cases involved Xp21, 6q23-24 and 13q22. Copy number changes of selected genes and a small deletion (156 kb) of the CDKN2B (p15) gene were confirmed by interphase cytogenetics and polymerase chain reaction analysis, respectively. Several gained regions included genes constitutively expressed in cHL. Among these, gains of STAT6 (12q13), NOTCH1 (9q34) and JUNB (19p13) were present in additional cHL with the usual low Hodgkin-Reed-Sternberg cell content.

Conclusions: The present study demonstrates that array comparative genomic hybridization of microdissected Hodgkin-Reed-Sternberg cells is suitable for identifying and characterizing chromosomal imbalances. Regions affected by genomic changes in Hodgkin-Reed-Sternberg cells recurrently include genes constitutively expressed in cHL.

Key words: Hodgkin’s lymphoma, array comparative genomic hybridization, microdissection.

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