Ramos Sandra, Molina Bertha, Navarrete-Meneses María Del Pilar, Cervantes-Barragan David E, Lozano Valentín, Frias Sara
Laboratorio de Citogenética, Instituto Nacional de Pediatría, Ciudad de Mexico 04530, Mexico.
Laboratorio de Genética y Cáncer, Instituto Nacional de Pediatría, Ciudad de Mexico 04530, Mexico.
Cancers (Basel). 2025 Jul 23;17(15):2437. doi: 10.3390/cancers17152437.
: Hodgkin's lymphoma (HL) affects 2-4 individuals per 100,000 annually. Standard treatment includes radiotherapy and ABVD chemotherapy, achieving a 95% survival rate. However, HL survivors face an elevated risk of treatment-related morbidity, particularly the development of secondary malignancies. Previous studies have demonstrated that ABVD treatment induces a high frequency of chromosomal aberrations (CAs) in lymphocytes from HL patients, with higher frequencies one year after treatment than during treatment. This study aimed to determine whether HL treatment also induces unclassified chromosomal/nuclear aberrations (UnCAs) in the lymphocytes of HL patients, and whether these alterations may serve as complementary indicators of genomic instability. : Peripheral blood lymphocytes from HL patients were collected at three time points: before treatment (BT), during treatment (DT), and one year after treatment (1yAT) with ABVD chemotherapy and radiotherapy. A minimum of 3000 nuclei were analyzed per patient to identify and quantify UnCAs. These results were compared to UnCA frequencies in healthy individuals. : The percentage of cells presenting UnCAs per 3000 nuclei was 23.92% BT, 18.58% DT, and 30.62% 1yAT. All values were significantly higher ( < 0.016) than the 8.16% observed in healthy controls. The increase was primarily driven by free chromatin and micronuclei clusters. UnCA frequency was lower during treatment than one year after, likely due to the elimination of highly damaged cells through apoptosis or lack of proliferative capacity. Over time, however, persistent genomic damage appears to accumulate in surviving cells, becoming more evident post-treatment. A parallel trend was observed between the frequencies of UnCAs free chromatin, micronucleus and micronuclei clusters, and classical CAs, showing a similar pattern of genomic damage induced by therapy. : The post-treatment increase in UnCAs indicates ongoing genomic instability, possibly driven by the selective survival of hematopoietic stem cells with higher genomic fitness. Given their persistence and association with therapy-induced damage, free chromatin and micronuclei clusters may serve as early biomarkers for secondary cancer risk in HL survivors.
霍奇金淋巴瘤（HL）每年每10万人中有2至4人患病。标准治疗包括放疗和ABVD化疗，生存率达95%。然而，HL幸存者面临与治疗相关的发病风险升高，尤其是继发性恶性肿瘤的发生。先前的研究表明，ABVD治疗可诱导HL患者淋巴细胞中高频的染色体畸变（CAs），治疗后一年的频率高于治疗期间。本研究旨在确定HL治疗是否也会在HL患者的淋巴细胞中诱导未分类的染色体/核畸变（UnCAs），以及这些改变是否可作为基因组不稳定的补充指标。
在三个时间点收集HL患者的外周血淋巴细胞：治疗前（BT）、治疗期间（DT）以及ABVD化疗和放疗后一年（1yAT）。每位患者至少分析3000个细胞核以识别和量化UnCAs。将这些结果与健康个体的UnCA频率进行比较。
每3000个细胞核中出现UnCAs的细胞百分比在BT时为23.92%，DT时为18.58%，1yAT时为30.62%。所有数值均显著高于健康对照中观察到的8.16%（<0.016）。增加主要由游离染色质和微核簇驱动。UnCA频率在治疗期间低于治疗后一年，可能是由于通过凋亡或缺乏增殖能力消除了高度受损的细胞。然而，随着时间的推移，持续的基因组损伤似乎在存活细胞中积累，在治疗后变得更加明显。在游离染色质、微核和微核簇的UnCA频率与经典CAs之间观察到平行趋势，显示出治疗诱导的基因组损伤的相似模式。
治疗后UnCAs的增加表明持续的基因组不稳定，可能由具有更高基因组适应性的造血干细胞的选择性存活驱动。鉴于游离染色质和微核簇的持续性以及与治疗诱导损伤的关联，它们可能作为HL幸存者继发性癌症风险的早期生物标志物。
