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: OBJECTIVE
  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
  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(-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.
authors.affiliation: Laboratoire de la Radiosensibilité des Tumeurs et des Tissus Sains, UPRES EA 27-10, Institut Gustave Roussy, Villejuif, France. mkacher@igr.fr
authors.forename: Radhia
authors.initials: R
authors.lastname: M'kacher
authors.forename: Annelise
authors.initials: A
authors.lastname: Bennaceur-Griscelli
authors.forename: Theodore
authors.initials: T
authors.lastname: Girinsky
authors.forename: Serge
authors.initials: S
authors.lastname: Koscielny
authors.forename: François
authors.initials: F
authors.lastname: Delhommeau
authors.forename: Julien
authors.initials: J
authors.lastname: Dossou
authors.forename: Dominique
authors.initials: D
authors.lastname: Violot
authors.forename: Evelyne
authors.initials: E
authors.lastname: Leclercq
authors.forename: Marie Hélène
authors.initials: MH
authors.lastname: Courtier
authors.forename: Nadine
authors.initials: N
authors.lastname: Béron-Gaillard
authors.forename: Elias
authors.initials: E
authors.lastname: Assaf
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.forename: Jean
authors.initials: J
authors.lastname: Bourhis
authors.forename: Daniele
authors.initials: D
authors.lastname: Feneux
authors.forename: Alain
authors.initials: A
authors.lastname: Bernheim
authors.forename: Claude
authors.initials: C
authors.lastname: Parmentier
authors.forename: Patrice
authors.initials: P
authors.lastname: Carde
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics; D002280:Basal Cell Carcinoma / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics*; D015331:Cohort Studies; D004260:DNA Repair; D005260:Female; D005500:Follow-Up Studies; D006689:Hodgkin Disease / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D006801:Humans; D008214:Lymphocytes / Q000473:pathology / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000209:etiology* / Q000235:genetics; D011446:Prospective Studies; D011836:Radiation Tolerance; D012878:Skin Neoplasms / Q000235:genetics; D017741:Survivors; D016615:Telomere / Q000473:pathology*