Clonal Evolution in t(14;18)-Positive Follicular Lymphoma, Evidence for Multiple Common Pathways, and Frequent Parallel Clonal Evolution
Clonal Evolution in t(14;18)-Positive Follicular Lymphoma, Evidence for Multiple Common Pathways, and Frequent Parallel Clonal Evolution
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DOI：
10.1158/1078-0432.ccr-08-0752
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发表时间：
2008-11-15
影响因子：
11.5
通讯作者：
Dave, Bhavana J.
中科院分区：
文献类型：
--
作者：
d'Amore, Francesco;Chan, Eric;Dave, Bhavana J.
目的：滤泡性淋巴瘤通常发生 t(14;18) 易位，但随后的额外细胞遗传学异常会导致疾病进展。该研究的主要目的是（a）确定t（14;18）阳性滤泡性淋巴瘤中细胞遗传学事件的频率和时间顺序，（b）确定滤泡性淋巴瘤的演变是否存在特定途径，（c）确定连续活检或单次活检中多个克隆的病例中的克隆分歧，以及（d）确定遗传失衡与临床结果的关联。滤泡性淋巴瘤的确诊和显示 t(14;18) (q32;q21) 的细胞遗传学分析均包括在内。对核型进行审查，并将细胞遗传学数据输入关系数据库以进行进一步的计算分析；对来自 360 名滤泡性淋巴瘤患者的 418 份活检样本进行了分析，其中包括 43 份连续活检样本。 结果：在仅存在一到两个基因组不平衡的病例中，最常见的染色体不平衡是 +7、del(6q)、+der(18)t(14;18)、+18 和 +X。这些异常也是分析所有核型时最常见的异常。相同（26%）和连续活检（63%）中的细胞遗传学异常克隆通常表现出遗传改变的差异。除t(14;18)以外的平衡易位并不常见，但涉及14q32、18q21、1p36、1q21、10q22、10q24和6q处大簇的染色体断裂相对频繁发生。 del (6q)、+5、+19 和 +20 与较差的总生存期相关，del (17p) 与较差的无事件生存期相关。低级别肿瘤（1 和 2）与较少的失衡相关。结论：我们的分析表明 +der(18)t(14;18) 可能是滤泡性淋巴瘤遗传进化的独特途径的切入点。其他常见的早期事件似乎提供了多个切入点，它们可能在滤泡性淋巴瘤的发病机制和进展中相互配合。来自同一患者的细胞遗传学异常克隆经常表现出遗传改变的差异，这表明前体克隆的平行进化是常见的事件。这项研究为进一步分析肿瘤进展的遗传途径提供了框架。
Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome.Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18) (q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed.Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del (6q), +5, +19, and +20 were associated with poorer overall survival, and del (17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances.Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.