Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Sweden.
Genes Chromosomes Cancer. 2012 Feb;51(2):196-206. doi: 10.1002/gcc.20944. Epub 2011 Nov 10.
Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as <10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrent-dup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
先前对唐氏综合征（ML-DS 和 DS-ALL）患儿的髓系和急性淋巴细胞白血病的细胞遗传学研究表明，此类病例与一般急性白血病的异常模式存在显著差异。此外，某些分子遗传学异常特征可用于区分与唐氏综合征相关的白血病，例如 ML-DS 中的 GATA1 突变和 DS-ALL 中的 CRLF2 基因失调。唐氏综合征和非唐氏综合征病例之间的微缺失/微重复是否也存在差异目前尚不清楚。为了解决这个问题，我们对 8 例儿科 ML-DS 和 17 例 B 细胞前体 DS-ALL 进行了单核苷酸多态性微阵列分析。在 ML-DS 病例中，共检测到 29 个不平衡（20 个增益和 9 个丢失）和两个部分单亲二倍体（pUPD）。没有一个小的（定义为<10 Mb）不平衡是复发性的，pUPD 也不是复发性的，而 18 个大的异常中，有 3 个是复发性的 dup(1q)、+8 和 +21。相比之下，在 DS-ALL 病例中鉴定出了几个频繁发生的变化，这些病例中存在 82 个不平衡（30 个增益和 52 个丢失）和四个 pUPD。在 40 个大的变化中，28 个是增益，12 个是丢失，其中包括+X、dup(Xq)、dup(1q)、del(7p)、dup(8q)、del(9p)、dup(9p)、del(12p)、dup(17q)和+21。在所鉴定的 40 个微缺失中，有几个靶向特定基因，以下基因重复缺失：BTG1 和 CDKN2A/B（29%的病例）、ETV6、IKZF1、PAX5 和 SERP2（18%）以及 BTLA、INPP4B、P2RY8 和 RB1（12%）。以前从未有报道过与白血病相关的 SERP2 和 INPP4B 基因缺失，这两个基因分别编码应激相关内质网蛋白家族成员 2 和肌醇多磷酸 4-磷酸酶-II。虽然其他基因的缺失与 ALL 相关，但 BTG1 缺失的频率很高是一个新发现。这些缺失可能是 DS-ALL 的一个临床亚群的特征，主要由年龄较大的男孩组成。总之，ML-DS 和 DS-ALL 在遗传学上是不同的，ML-DS 主要是增益，而 DS-ALL 主要是缺失。此外，DS-ALL 的特征是存在多个复发性基因缺失，BTG1 缺失尤其频繁。
