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.
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.
M'kacher
Radhia
R
Laboratoire de la Radiosensibilité des Tumeurs et des Tissus Sains, UPRES EA 27-10, Institut Gustave Roussy, Villejuif, France. mkacher@igr.fr
Bennaceur-Griscelli
Annelise
A
Girinsky
Theodore
T
Koscielny
Serge
S
Delhommeau
François
F
Dossou
Julien
J
Violot
Dominique
D
Leclercq
Evelyne
E
Courtier
Marie Hélène
MH
Béron-Gaillard
Nadine
N
Assaf
Elias
E
Ribrag
Vincent
V
Bourhis
Jean
J
Feneux
Daniele
D
Bernheim
Alain
A
Parmentier
Claude
C
Carde
Patrice
P
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*