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Cancers 2018, 10(7), 233; https://doi.org/10.3390/cancers10070233

Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability

1
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France
2
IRIMAS, Institut de Recherche en Informatique, Mathématiques, Automatique et Signal, Université de Haute-Alsace, 68093 Mulhouse, France
3
Department of Genetic, Groupe Hospitalier de la Région de Mulhouse Sud-Alsace, 68093 Mulhouse, France
4
Institute of Biomedicine, University of Aarhus, DK-8000 Aarhus, Denmark
5
Laboratory of Biochemistry B, Saint Louis Hospital, 75010 Paris, France
6
Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Techology, 44-100 Gliwice, Poland
7
Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Didcot OX11 ORQ, UK
8
Department of Radiation Oncology, Gustave Roussy Cancer Campus, 94805 Villejuif, France
9
Department of Medicine, Gustave Roussy Cancer Campus, University Paris Saclay, 94805 Villejuif, France
10
Cell Environment DNA Damages R&D Oncology Section, 75020 Paris, France
This paper is dedicated to the memory of Dr. Alain Bernheim.
*
Author to whom correspondence should be addressed.
Received: 1 April 2018 / Revised: 29 June 2018 / Accepted: 3 July 2018 / Published: 13 July 2018
(This article belongs to the Special Issue Hodgkin's Lymphoma)
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Abstract

Background: Microsatellite and chromosomal instability have been investigated in Hodgkin lymphoma (HL). Materials and Methods: We studied seven HL cell lines (five Nodular Sclerosis (NS) and two Mixed Cellularity (MC)) and patient peripheral blood lymphocytes (100 NS-HL and 23 MC-HL). Microsatellite instability (MSI) was assessed by PCR. Chromosomal instability and telomere dysfunction were investigated by FISH. DNA repair mechanisms were studied by transcriptomic and molecular approaches. Results: In the cell lines, we observed high MSI in L428 (4/5), KMH2, and HDLM2 (3/5), low MSI in L540, L591, and SUP-HD1, and none in L1236. NS-HL cell lines showed telomere shortening, associated with alterations of nuclear shape. Small cells were characterized by telomere loss and deletion, leading to chromosomal fusion, large nucleoplasmic bridges, and breakage/fusion/bridge (B/F/B) cycles, leading to chromosomal instability. The MC-HL cell lines showed substantial heterogeneity of telomere length. Intrachromosmal double strand breaks induced dicentric chromosome formation, high levels of micronucleus formation, and small nucleoplasmic bridges. B/F/B cycles induced complex chromosomal rearrangements. We observed a similar pattern in circulating lymphocytes of NS-HL and MC-HL patients. Transcriptome analysis confirmed the differences in the DNA repair pathways between the NS and MC cell lines. In addition, the NS-HL cell lines were radiosensitive and the MC-cell lines resistant to apoptosis after radiation exposure. Conclusions: In mononuclear NS-HL cells, loss of telomere integrity may present the first step in the ongoing process of chromosomal instability. Here, we identified, MSI as an additional mechanism for genomic instability in HL. View Full-Text
Keywords: Hodgkin lymphoma; chromosomal instability; telomere dysfunction; dicentric; MSI; P53 Hodgkin lymphoma; chromosomal instability; telomere dysfunction; dicentric; MSI; P53
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Cuceu, C.; Colicchio, B.; Jeandidier, E.; Junker, S.; Plassa, F.; Shim, G.; Mika, J.; Frenzel, M.; AL Jawhari, M.; Hempel, W.M.; O’Brien, G.; Lenain, A.; Morat, L.; Girinsky, T.; Dieterlen, A.; Polanska, J.; Badie, C.; Carde, P.; M’Kacher, R. Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability . Cancers 2018, 10, 233.

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