Cytogenetics Laboratory, Department of Hematology/Stem Cell Transplantation, City of Hope, Duarte, California 91010, USA.
Clin Cancer Res. 2011 May 15;17(10):3443-54. doi: 10.1158/1078-0432.CCR-10-1071. Epub 2011 Mar 8.
To determine the recurring DNA copy number alterations (CNA) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture microdissected CD30(+) Hodgkin and Reed-Sternberg (HRS) cells.
Archived tissues from 27 CD30(+) HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared with the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease).
Gains and losses observed in more than 35% of HL samples were localized to 22 and 12 chromosomal regions, respectively. Frequent gains (>65%) were associated with growth and proliferation, NF-κB activation, cell-cycle control, apoptosis, and immune and lymphoid development. Frequent losses (>40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, and ID4, inhibitor of DNA binding 4), transcriptional repressors (TXNIP, thioredoxin interacting protein), SKP2 (S-phase kinase-associated protein 2; ubiquitin ligase component), and an antagonist of NF-κB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, and SKP2), and gains in 7q36 (SHH, sonic hedgehog homolog) and 9q34 (ABL1, CDK9, LCN2, and PTGES). Gains (>35%) in the HL chemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4, and IL10), whereas the refractory samples showed frequent loss of 4q27 (interleukin; IL21/IL2) and 17p12, and gain of 19q13.3 (BCL3/RELB).
We identified nonrandom CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL.
通过使用激光捕获显微切割 CD30(+)霍奇金和 Reed-Sternberg (HRS) 细胞的基于微阵列的比较基因组杂交 (aCGH)，确定经典霍奇金淋巴瘤 (HL) 中的反复出现的 DNA 拷贝数改变 (CNA)。
使用 DNA 微阵列分析 27 例 CD30(+)HL 加对照样本的存档组织。HL 分子核型与生发中心 B 细胞的基因组图谱和治疗结果（化疗反应与原发性难治性疾病）进行比较。
在超过 35%的 HL 样本中观察到的增益和缺失分别定位于 22 和 12 个染色体区域。高频增益 (>65%)与生长和增殖、NF-κB 激活、细胞周期控制、凋亡以及免疫和淋巴发育有关。高频缺失 (>40%)包括肿瘤抑制基因 (SPRY1、NELL1 和 ID4，DNA 结合抑制剂 4)、转录抑制因子 (TXNIP、硫氧还蛋白相互作用蛋白)、SKP2(S 期激酶相关蛋白 2；泛素连接酶成分) 和 NF-κB 激活拮抗剂 (PPARGC1A)。与生发中心图谱相比，HL 中最常见的不平衡是 5p13 缺失 (AMACR、GDNF 和 SKP2) 和 7q36 增益 (SHH， sonic hedgehog 同源物) 和 9q34 增益 (ABL1、CDK9、LCN2 和 PTGES)。HL 化疗反应患者的增益 (>35%)中包含已知调节 T 细胞迁移或 NF-κB 激活的基因 (CCL22、CX3CL1、CCL17、DOK4 和 IL10)，而难治性样本则显示出频繁的 4q27(白细胞介素；IL21/IL2) 和 17p12 缺失以及 19q13.3 增益 (BCL3/RELB)。
我们确定了经典 HL 分子核型中的非随机 CNA。一些反复出现的遗传病变与疾病结果相关。这些发现可能对患者的咨询和管理以及原发性难治性 HL 的新型治疗方法的开发有用的预后标志物。
