Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Genes Chromosomes Cancer. 2013 Jun;52(6):564-79. doi: 10.1002/gcc.22054. Epub 2013 Mar 18.
Near haploidy (23-29 chromosomes) is a numerical cytogenetic aberration in childhood acute lymphoblastic leukemia (ALL) associated with particularly poor outcome. In contrast, high hyperdiploidy (51-67 chromosomes) has a favorable prognosis. Correct classification and appropriate risk stratification of near haploidy is frequently hampered by the presence of apparently high hyperdiploid clones that arise by endoreduplication of the original near haploid clone. We evaluated next-generation-sequencing (NGS) to distinguish between "high hyperdiploid" leukemic clones of near haploid and true high hyperdiploid origin. Five high hyperdiploid ALL cases and the "high hyperdiploid" cell line MHH-CALL-2, derived from a near haploid clone, were tested for uniparental isodisomy. NGS showed that all disomic chromosomes of MHH-CALL-2, but none of the patients, were of uniparental origin, thus reliably discriminating these subtypes. Whole-exome- and whole-genome-sequencing of MHH-CALL-2 revealed homozygous non-synonymous coding mutations predicted to be deleterious for the protein function of 63 genes, among them known cancer-associated genes, such as FANCA, NF1, TCF7L2, CARD11, EP400, histone demethylases, and transferases (KDM6B, KDM1A, PRDM11). Only eight of these were also, but heterozygously, mutated in the high hyperdiploid patients. Structural variations in MHH-CALL-2 include a homozygous deletion (MTAP/CDKN2A/CDKN2B/ANRIL), a homozygous inversion (NCKAP5), and an unbalanced translocation (FAM189A1). Together, the sequence variations provide MHH-CALL-2 with capabilities typically acquired during cancer development, e.g., loss of cell cycle control, enhanced proliferation, lack of DNA repair, cell death evasion, and disturbance of epigenetic gene regulation. Poorer prognosis of near haploid ALL most likely results from full penetrance of a large array of detrimental homozygous mutations.
近单体性（23-29 条染色体）是儿童急性淋巴细胞白血病（ALL）中的一种染色体数目细胞遗传学异常，与预后特别差有关。相比之下，高超二倍体性（51-67 条染色体）具有良好的预后。近单体性的正确分类和适当的风险分层经常受到似乎是高超二倍体克隆的阻碍，这些克隆是由原始近单体克隆的内复制产生的。我们评估了下一代测序（NGS）以区分近单体性和真正高超二倍体起源的“高超二倍体”白血病克隆。对五个高超二倍体 ALL 病例和源自近单体性克隆的“高超二倍体”细胞系 MHH-CALL-2 进行了单亲二体性检测。NGS 显示，MHH-CALL-2 的所有二倍体染色体均来自单亲，而患者无一例外地来自单亲，从而可靠地区分了这些亚型。MHH-CALL-2 的全外显子组和全基因组测序显示，同源纯合的非同义编码突变，这些突变预计会对 63 个基因的蛋白质功能造成有害影响，其中包括已知的癌症相关基因，如 FANCA、NF1、TCF7L2、CARD11、EP400、组蛋白去甲基酶和转移酶（KDM6B、KDM1A、PRDM11）。这些基因中只有 8 个在高超二倍体患者中也是杂合突变。MHH-CALL-2 的结构变异包括纯合缺失（MTAP/CDKN2A/CDKN2B/ANRIL）、纯合倒位（NCKAP5）和不平衡易位（FAM189A1）。这些序列变异共同赋予了 MHH-CALL-2 通常在癌症发展过程中获得的能力，例如细胞周期控制丧失、增殖增强、缺乏 DNA 修复、逃避细胞死亡和干扰表观遗传基因调控。近单体性 ALL 的预后较差可能是由于大量有害纯合突变的完全外显。
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