M'kacher Radhia, Bennaceur-Griscelli Annelise, Girinsky Theodore, Koscielny Serge, Delhommeau François, Dossou Julien, Violot Dominique, Leclercq Evelyne, Courtier Marie Hélène, Béron-Gaillard Nadine, Assaf Elias, Ribrag Vincent, Bourhis Jean, Feneux Daniele, Bernheim Alain, Parmentier Claude, Carde Patrice
Laboratoire de la Radiosensibilité des Tumeurs et des Tissus Sains, UPRES EA 27-10, Institut Gustave Roussy, Villejuif, France.
Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):465-71. doi: 10.1016/j.ijrobp.2007.01.050. Epub 2007 Apr 6.
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.
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.
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.
An intimate relationship between pre-treatment telomere shortening, chromosomal instability, radiation sensitivity and occurrence of SC was found in HL patients.
探讨霍奇金淋巴瘤（HL）患者端粒长度、染色体不稳定性与第二原发癌（SC）发生之间的潜在联系，已知HL患者有发生SC的风险。本研究基于端粒功能障碍和DNA修复途径与许多病理状况相关这一发现。
对三组HL患者进行了研究：73例诊断后接受前瞻性随访超过5年的患者（前瞻性HL队列），28例发生SC的患者（SC HL队列），以及18例自初始治疗后无疾病或并发症证据的长期幸存者（无疾病证据HL队列）。通过端粒限制性片段分析对外周血淋巴细胞中的端粒长度进行分析。30名健康供者和70例新诊断实体瘤患者作为对照人群。
与对照组相比，前瞻性HL队列的患者在任何治疗前显示出与年龄无关的较短端粒（平均值，健康供者为8.3 kb，HL患者为11.7 kb；HL患者中18%<6 kb）、自发染色体异常增加以及体外辐射敏感性增加（每项p<10-4）。治疗后，端粒缩短与以复杂染色体重排和克隆畸变持续存在为特征的细胞遗传学图谱相关。此外，前瞻性HL患者中的两例SC最初具有短端粒和复杂染色体重排。此外，SC HL队列的特征是端粒明显缩短（无疾病证据HL队列为6.6 kb，SC HL队列为9.7 kb）、存在复杂染色体重排以及体外辐射敏感性增加。
在HL患者中发现治疗前端粒缩短、染色体不稳定性、辐射敏感性与SC发生之间存在密切关系。
