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Cancers (Basel). 2018 Jul 13;10(7). pii: E233. doi: 10.3390/cancers10070233.

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

Author information

1
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France. cuceu_corina@yahoo.com.
2
IRIMAS, Institut de Recherche en Informatique, Mathématiques, Automatique et Signal, Université de Haute-Alsace, 68093 Mulhouse, France. bruno.colicchio@uha.fr.
3
Department of Genetic, Groupe Hospitalier de la Région de Mulhouse Sud-Alsace, 68093 Mulhouse, France. jeandidiere@ghrmsa.fr.
4
Institute of Biomedicine, University of Aarhus, DK-8000 Aarhus, Denmark. sjunker@biomed.au.dk.
5
Laboratory of Biochemistry B, Saint Louis Hospital, 75010 Paris, France. lfplassa@yahoo.fr.
6
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France. graceshim1@gmail.com.
7
Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Techology, 44-100 Gliwice, Poland. justyna.mika@polsl.pl.
8
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France. monika.frenzel@hotmail.com.
9
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France. mustafa.aljawhari@hotmail.fr.
10
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France. williamhempel824@gmail.com.
11
Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Didcot OX11 ORQ, UK. Grainne.o'brien@phe.gov.uk.
12
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France. audelenain@yahoo.fr.
13
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France. luc.morat@cea.fr.
14
Department of Radiation Oncology, Gustave Roussy Cancer Campus, 94805 Villejuif, France. theogirinsky@me.com.
15
IRIMAS, Institut de Recherche en Informatique, Mathématiques, Automatique et Signal, Université de Haute-Alsace, 68093 Mulhouse, France. alain.dieterlen@uha.fr.
16
Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Techology, 44-100 Gliwice, Poland. Joanna.Polanska@polsl.pl.
17
Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Didcot OX11 ORQ, UK. christophe.badie@phe.gov.uk.
18
Department of Medicine, Gustave Roussy Cancer Campus, University Paris Saclay, 94805 Villejuif, France. dr.pcarde@gmail.com.
19
Radiobiology and Oncology Laboratory, CEA, iRCM, 92265 Fontenay aux Roses CEDEX, France. radhia.mkacher@gmail.com.
20
Cell Environment DNA Damages R&D Oncology Section, 75020 Paris, France. radhia.mkacher@gmail.com.

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.

KEYWORDS:

Hodgkin lymphoma; MSI; P53; chromosomal instability; dicentric; telomere dysfunction

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