PDF(Pubmed)
Abstract：
Ring chromosomes (RC) are present in <10% of patients with hematological malignancies and are associated with poor prognosis. Until now, only small cohorts of patients with hematological neoplasms and concomitant RCs have been cytogenetically characterized. Here, we performed a conventional chromosome analysis on metaphase spreads from >13,000 patients diagnosed with hematological malignancies at the Johns Hopkins University Hospital and identified 98 patients with RCs-90 with myeloid malignancies and 8 with lymphoid malignancies. We also performed a targeted Next-Generation Sequencing (NGS) assay, using a panel of 642 cancer genes, to identify whether these patients harbor relevant pathogenic variants. Cytogenetic analyses revealed that RCs and marker chromosomes of unknown origin are concurrently present in most patients by karyotyping, and 93% of patients with NGS data have complex karyotypes. A total of 72% of these individuals have pathogenic mutations in TP53, most of whom also possess cytogenetic abnormalities resulting in the loss of 17p, including the loss of TP53. All patients with a detected RC and without complex karyotypes also lack TP53 mutations but have pathogenic mutations in TET2. Further, 70% of RCs that map to a known chromosome are detected in individuals without TP53 mutations. Our data suggest that RCs in hematological malignancies may arise through different mechanisms, but ultimately promote widespread chromosomal instability.
摘要：
环状染色体（RC）存在于<10％的血液系统恶性肿瘤患者中，并与不良预后相关。直到现在,只有一小部分血液肿瘤和合并RCs的患者进行了细胞遗传学鉴定.这里,我们对约翰霍普金斯大学医院诊断为血液系统恶性肿瘤的>13,000例患者的中期传播进行了常规染色体分析,确定了98例RCs-90患者为髓系恶性肿瘤,8例患者为淋巴系统恶性肿瘤.我们还进行了靶向下一代测序（NGS）测定，使用一组642个癌症基因，以确定这些患者是否有相关的致病变异。细胞遗传学分析显示，通过核型分析，大多数患者同时存在RCs和未知来源的标记染色体，93%的NGS患者具有复杂的核型。这些个体中有72％在TP53中具有致病性突变，其中大多数还具有导致17p丢失的细胞遗传学异常，包括TP53的损失。所有检测到RC且没有复杂核型的患者也缺乏TP53突变，但在TET2中有致病性突变。Further,在没有TP53突变的个体中检测到70%映射到已知染色体的RC。我们的数据表明，血液系统恶性肿瘤中的RCs可能通过不同的机制产生，但最终导致广泛的染色体不稳定。
