Cancer Genomics Group, Cancer Sciences Division, School of Medicine, University of Southampton, Southampton, UK.
Leukemia. 2011 Mar;25(3):489-97. doi: 10.1038/leu.2010.288. Epub 2010 Dec 10.
Historically, genes targeted by recurrent chromosomal deletions have been identified within the smallest genomic region shared in all patients, the minimally deleted region (MDR). However, deletions this small do not occur in all patients and are a simplification of the impact larger heterogeneous deletions have during carcinogenesis. We use the example of 13q14 deletions in chronic lymphocytic leukemia to show that genes outside MDRs are associated with disease progression. Genomic profiling of 224 patients identified 205 copy number alterations on chromosome 13 in 132 cases. Deletions including DLEU2 were heterogeneous (845 Kb-96.2 Mb) and identified two breakpoint cluster regions within short interspersed nuclear elements proximal to DLEU2 and within long interspersed nuclear elements/L1 repeats distal to GUCY1B2. After defining a deletion class on the basis of size and location, we show that (a) at diagnosis, larger deletions (class II) were associated with a significantly increased risk of disease progression (odds ratio=12.3; P=0.005), (b) in progressive patients, class II deletions were enriched (P=0.02) and (c) this association was independent of IgVH mutational status, ZAP70 expression and ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2-49.2 Mb), including SETDB2, PHF11 and RCBTB1, was significantly associated (P<0.01) with disease progression. Here, we show that the deletion of genes outside MDRs can influence clinical outcome.
从历史上看，在所有患者中共有的最小基因组区域（最小缺失区域 [MDR]）中鉴定出了受反复染色体缺失靶向的基因。然而，如此小的缺失并非在所有患者中都发生，并且是对在癌变过程中较大异质缺失的影响的简化。我们以慢性淋巴细胞白血病 13q14 缺失为例，表明 MDR 外的基因与疾病进展有关。对 224 名患者的基因组谱分析在 132 例病例中鉴定出染色体 13 上的 205 个拷贝数改变。包括 DLEU2 在内的缺失是异质的（845 Kb-96.2 Mb），并在 DLEU2 附近的短散布核元件和 GUCY1B2 远端的长散布核元件/L1 重复内鉴定出两个断点簇区域。在基于大小和位置定义缺失类别后，我们表明：(a) 在诊断时，较大的缺失（类别 II）与疾病进展的风险显著增加相关（优势比=12.3；P=0.005），(b) 在进展患者中，富集了类别 II 缺失（P=0.02），(c) 这种关联独立于 IgVH 突变状态、ZAP70 表达和 ATM/TP53 缺失。包括 SETDB2、PHF11 和 RCBTB1 在内的 1 Mb 基因簇（48.2-49.2 Mb）的缺失与疾病进展显著相关（P<0.01）。在这里，我们表明 MDR 外基因的缺失会影响临床结果。
