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Title: Telomere Shortening and Associated Chromosomal Instability in Peripheral Blood Lymphocytes of Patients With Hodgkin's Lymphoma Prior to Any Treatment Are Predictive of Second Cancers

Abstract

Purpose: To investigate a potential link between telomere length, chromosomal instability, and the advent of a second cancer (SC) in patients with Hodgkin's lymphoma (HL), who are known to be at risk for SCs. This study was premised on the finding that telomere dysfunction and DNA repair pathways were related to many pathologic conditions. Methods and Materials: Three cohorts of patients with HL were studied: 73 who were prospectively followed >5 years after diagnosis (prospective HL cohort), 28 who developed a SC (SC HL cohort), and 18 long-term survivors with no evidence of disease or complication since their initial treatment (NED HL cohort). Telomere length was analyzed by a telomeric restriction fragment assay in peripheral blood lymphocytes. Thirty healthy donors and 70 patients with a newly diagnosed solid tumor were the control population. Results: Compared with controls, patients from the prospective HL cohort, before any treatment, showed age-independent shorter telomeres (mean, 8.3 vs. 11.7 kb in healthy donors; <6 kb in 18% in HL patients), increased spontaneous chromosomal abnormalities, and increased in vitro radiation sensitivity (p < 10{sup -4} each). After treatment, telomere shortening was associated with cytogenetic profiles characterized by the persistence of complex chromosomal rearrangement and clonal aberrations.more » Moreover, the two cases of SC in the prospective HL patients had short telomeres and CCR initially. In addition, the SC HL cohort was characterized by markedly short telomeres (6.6 vs. 9.7 kb in the NED HL cohort), the presence of complex chromosome rearrangements, and increased in vitro radiation sensitivity. Conclusions: An intimate relationship between pre-treatment telomere shortening, chromosomal instability, radiation sensitivity and occurrence of SC was found in HL patients.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [6];  [7];  [7]; ;  [2];  [7]; ; ;  [8];  [9];  [10];  [11];  [7]
  1. Laboratoire de la Radiosensibilite des Tumeurs et des Tissus Sains, UPRES EA 27-10, Institut Gustave Roussy, Villejuif (France). E-mail: mkacher@igr.fr
  2. Departement de la Biologie Clinique, Institut Gustave Roussy, Villejuif (France)
  3. Departement de Radiotherapie, Institut Gustave Roussy, Villejuif (France)
  4. Departement de Bio-Statistique, Institut Gustave Roussy, Villejuif (France)
  5. Inserm U790, Institut Gustave Roussy, Villejuif (France)
  6. (France)
  7. Laboratoire de la Radiosensibilite des Tumeurs et des Tissus Sains, UPRES EA 27-10, Institut Gustave Roussy, Villejuif (France)
  8. Departement de Medecine, Institut Gustave Roussy, Villejuif (France)
  9. Laboratoire de la Radiosensibilite des Tumeurs et des Tissus Sains, UPRES EA 27-10, Institut Gustave Roussy, Villejuif (France)|[Departement de Radiotherapie, Institut Gustave Roussy, Villejuif (France)
  10. Service d'Hematologie et de Cytogenetique, Hopital de Bicetre, Le Kremlin-Bicetre (France)
  11. Cellular Genomics of Cancer Laboratory CNRS-UMR 1599, Institut Gustave Roussy, Villejuif (France)
Publication Date:
OSTI Identifier:
20951666
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 68; Journal Issue: 2; Other Information: DOI: 10.1016/j.ijrobp.2007.01.050; PII: S0360-3016(07)00242-8; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; CHROMOSOMES; DIAGNOSIS; DNA REPAIR; IN VITRO; LYMPHOCYTES; LYMPHOMAS; PATIENTS; SENSITIVITY; TELOMERES

Citation Formats

M'kacher, Radhia, Bennaceur-Griscelli, Annelise, Girinsky, Theodore, Koscielny, Serge, Delhommeau, Francois, Laboratoire d'Immunologie Hematologie, Hopital Saint-Antoine, Universite Pierre et Marie Curie, Paris, Dossou, Julien, Violot, Dominique, Leclercq, Evelyne, Courtier, Marie Helene, Beron-Gaillard, Nadine, Assaf, Elias, Ribrag, Vincent, Carde, Patrice, Bourhis, Jean, Feneux, Daniele, Bernheim, Alain, and Parmentier, Claude. Telomere Shortening and Associated Chromosomal Instability in Peripheral Blood Lymphocytes of Patients With Hodgkin's Lymphoma Prior to Any Treatment Are Predictive of Second Cancers. United States: N. p., 2007. Web. doi:10.1016/j.ijrobp.2007.01.050.
M'kacher, Radhia, Bennaceur-Griscelli, Annelise, Girinsky, Theodore, Koscielny, Serge, Delhommeau, Francois, Laboratoire d'Immunologie Hematologie, Hopital Saint-Antoine, Universite Pierre et Marie Curie, Paris, Dossou, Julien, Violot, Dominique, Leclercq, Evelyne, Courtier, Marie Helene, Beron-Gaillard, Nadine, Assaf, Elias, Ribrag, Vincent, Carde, Patrice, Bourhis, Jean, Feneux, Daniele, Bernheim, Alain, & Parmentier, Claude. Telomere Shortening and Associated Chromosomal Instability in Peripheral Blood Lymphocytes of Patients With Hodgkin's Lymphoma Prior to Any Treatment Are Predictive of Second Cancers. United States. doi:10.1016/j.ijrobp.2007.01.050.
M'kacher, Radhia, Bennaceur-Griscelli, Annelise, Girinsky, Theodore, Koscielny, Serge, Delhommeau, Francois, Laboratoire d'Immunologie Hematologie, Hopital Saint-Antoine, Universite Pierre et Marie Curie, Paris, Dossou, Julien, Violot, Dominique, Leclercq, Evelyne, Courtier, Marie Helene, Beron-Gaillard, Nadine, Assaf, Elias, Ribrag, Vincent, Carde, Patrice, Bourhis, Jean, Feneux, Daniele, Bernheim, Alain, and Parmentier, Claude. Fri . "Telomere Shortening and Associated Chromosomal Instability in Peripheral Blood Lymphocytes of Patients With Hodgkin's Lymphoma Prior to Any Treatment Are Predictive of Second Cancers". United States. doi:10.1016/j.ijrobp.2007.01.050.
@article{osti_20951666,
title = {Telomere Shortening and Associated Chromosomal Instability in Peripheral Blood Lymphocytes of Patients With Hodgkin's Lymphoma Prior to Any Treatment Are Predictive of Second Cancers},
author = {M'kacher, Radhia and Bennaceur-Griscelli, Annelise and Girinsky, Theodore and Koscielny, Serge and Delhommeau, Francois and Laboratoire d'Immunologie Hematologie, Hopital Saint-Antoine, Universite Pierre et Marie Curie, Paris and Dossou, Julien and Violot, Dominique and Leclercq, Evelyne and Courtier, Marie Helene and Beron-Gaillard, Nadine and Assaf, Elias and Ribrag, Vincent and Carde, Patrice and Bourhis, Jean and Feneux, Daniele and Bernheim, Alain and Parmentier, Claude},
abstractNote = {Purpose: To investigate a potential link between telomere length, chromosomal instability, and the advent of a second cancer (SC) in patients with Hodgkin's lymphoma (HL), who are known to be at risk for SCs. This study was premised on the finding that telomere dysfunction and DNA repair pathways were related to many pathologic conditions. Methods and Materials: Three cohorts of patients with HL were studied: 73 who were prospectively followed >5 years after diagnosis (prospective HL cohort), 28 who developed a SC (SC HL cohort), and 18 long-term survivors with no evidence of disease or complication since their initial treatment (NED HL cohort). Telomere length was analyzed by a telomeric restriction fragment assay in peripheral blood lymphocytes. Thirty healthy donors and 70 patients with a newly diagnosed solid tumor were the control population. Results: Compared with controls, patients from the prospective HL cohort, before any treatment, showed age-independent shorter telomeres (mean, 8.3 vs. 11.7 kb in healthy donors; <6 kb in 18% in HL patients), increased spontaneous chromosomal abnormalities, and increased in vitro radiation sensitivity (p < 10{sup -4} each). After treatment, telomere shortening was associated with cytogenetic profiles characterized by the persistence of complex chromosomal rearrangement and clonal aberrations. Moreover, the two cases of SC in the prospective HL patients had short telomeres and CCR initially. In addition, the SC HL cohort was characterized by markedly short telomeres (6.6 vs. 9.7 kb in the NED HL cohort), the presence of complex chromosome rearrangements, and increased in vitro radiation sensitivity. Conclusions: An intimate relationship between pre-treatment telomere shortening, chromosomal instability, radiation sensitivity and occurrence of SC was found in HL patients.},
doi = {10.1016/j.ijrobp.2007.01.050},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 2,
volume = 68,
place = {United States},
year = {Fri Jun 01 00:00:00 EDT 2007},
month = {Fri Jun 01 00:00:00 EDT 2007}
}
  • Blood lymphocytes from 10 untreated patients with active Hodgkin's disease were compared with those of 10 cured patients with regard to the responsiveness of the cells to PHA and Con A following in vitro irradiation. Lymphocytes of patients remaining in long-term remission exhibited the same pattern of radiosensitivity as those of healthy donors: there was one relatively radiosensitive cell population and one relatively resistant. The latter cell population was undetectable in patients with an active disease. Reappearance of the radioresistant PHA and Con A reactive cell fractions might thus be associated with remission.
  • Total lymphocyte counts, and the percentage of T and B lymphocytes and monocytes in untreated patients with Hodgkin's disease were not significantly different from those observed in normal donors. At the completion of radiotherapy, the mean total lymphocyte count of 503/mm3 was 4 SD below the mean for normal controls. Although a group of 26 patients in continuous complete remission from 12 to 111 months after radiation treatment regained normal total numbers of lymphocytes and monocytes, they exhibited a striking T lymphocytopenia and B lymphocytosis. Concomitantly, there was a significant increase of null (neither T nor B) lymphocytes. The responsemore » of peripheral blood lymphocytes to phytohemagglutinin, concanavalin A, and tetanus toxoid before treatment was significantly impaired. 1 to 10 yr after completion of treatment, there seemed to be little or no recovery of these responses. The capacity of peripheral blood lymphocytes to respond to allo-antigens on foreign lymphocytes in vitro (mixed lymphocyte reaction) was normal in nine untreated patients. However, the mixed lymphocyte reaction was markedly impaired during the first 2 yr after treatment. There was a partial and progressive restoration of the mixed lymphocyte reaction during the next 3 yr, and normal responses were observed in patients in continuous complete remission for 5 yr or more. The in vivo response to dinitrochlorobenzene was also examined. 88 percent (15/17) of patients initially sensitive to dinitrochlorobenzene were anergic to the allergen at the completion of a course of radiotherapy, but nine of these regained their hypersensitivity response during the 1st yr after treatment. The restoration of cell mediated immune functions after radiotherapy is time dependent and its kinetics may differ for various T-cell functions.« less
  • Purpose: The chromosomal radiosensitivity in peripheral blood lymphocytes of cancer patients was reported to be higher than that of healthy donors. This effect is especially prominent when aberrations induced in the G{sub 2} phase of the cell cycle are analyzed. The aim of our study was to investigate if the G{sub 2} aberration frequencies in lymphocytes of patients with larynx cancer are higher than in the case of control individuals. Also, we tested if the frequencies of G{sub 2} aberrations correlate with side effects of radiotherapy. Methods and Materials: Peripheral blood of 38 patients was collected before the onset ofmore » radiotherapy, cultured for 72 h, and irradiated with 2 Gy after 67 h. Lymphocytes of 40 healthy donors were treated in the same way. Results: The spontaneous and radiation-induced aberration frequencies in lymphocytes of patients were on average higher than in those of healthy donors. No statistically significant correlation was observed between aberration frequencies in lymphocytes and the degree of both early and late normal tissue reactions. Conclusions: The chromosomal radiosensitivity of lymphocytes of patients with larynx cancer may be a marker of cancer predisposition; however, it does not appear to have a predictive value for the risk of developing side effects to radiotherapy.« less
  • The risk of second malignancies following non-Hodgkin's lymphoma (NHL) was estimated in 29,153 patients diagnosed with NHL between 1973 and 1987 in one of nine areas participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Compared with the general population, NHL patients were at a significantly increased risk of developing second cancers (observed/expected (O/E) = 1.18; O = 1231). The O/E ratio increased significantly with time to reach 1.77 in 10-year survivors. Significant excesses were noted for acute nonlymphocytic leukemia (O/E = 2.88), cancers of the bladder (O/E = 1.30), kidney (O/E = 1.47), and lung (O/Emore » = 1.57), malignant melanoma (O/E = 2.44), and Hodgkin's disease (O/E = 4.16). Chemotherapy appeared related to subsequent acute nonlymphocytic leukemia (ANLL) and bladder cancer. Radiation therapy was associated with ANLL and possibly cancers of the lung, bladder, and bone. Malignant melanoma was not clearly related to initial NHL treatment.« less