Schwartz Jason R, Walsh Michael P, Ma Jing, Lamprecht Tamara, Wang Shuoguo, Wu Gang, Raimondi Susana, Triplett Brandon M, Klco Jeffery M
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cold Spring Harb Mol Case Stud. 2018 Oct 1;4(5). doi: 10.1101/mcs.a002980. Print 2018 Oct.
Donor-derived hematologic malignancies are rare complications of hematopoietic cell transplantation (HCT). Although these are commonly either a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), in general, they are a heterogeneous group of diseases, and a unified mechanism for their development has remained elusive. Here we report next-generation sequencing, including whole-exome sequencing (WES), whole-genome sequencing (WGS), and targeted sequencing, of a case of donor-derived MDS (dMDS) following HCT for high-risk B-lymphoblastic leukemia (B-ALL) in an adolescent. Through interrogation of single-nucleotide polymorphisms (SNPs) in the WGS data, we unequivocally prove that the MDS is donor-derived. Additionally, we sequenced 15 samples from 12 time points, including the initial B-ALL diagnostic sample through several post-HCT remission samples, the dMDS, and representative germline samples from both patient and donor, to show that the MDS-related pathologic mutations, including a canonical (p.Y700*) mutation, were detectable nearly 3 yr prior to the morphological detection of MDS. Furthermore, these MDS mutations were not detectable immediately following, and for >1 yr post-, HCT. These data support the clinical utility of comprehensive sequencing following HCT to detect donor-derived malignancies, while providing insights into the clonal progression of dMDS over a 4-yr period.
供者来源的血液系统恶性肿瘤是造血细胞移植（HCT）罕见的并发症。虽然这些通常是骨髓增生异常综合征（MDS）或急性髓系白血病（AML），但总体而言，它们是一组异质性疾病，其发生发展的统一机制仍不清楚。在此，我们报告了一名青少年高危B淋巴细胞白血病（B-ALL）患者接受HCT后发生供者来源的MDS（dMDS）病例的二代测序结果，包括全外显子组测序（WES）、全基因组测序（WGS）和靶向测序。通过对WGS数据中的单核苷酸多态性（SNP）进行分析，我们明确证实该MDS是供者来源的。此外，我们对来自12个时间点的15个样本进行了测序，包括最初的B-ALL诊断样本、多个HCT后缓解样本、dMDS样本以及患者和供者的代表性种系样本，结果显示与MDS相关的病理突变，包括一个典型的（p.Y700*）突变，在MDS形态学检测前近3年就已可检测到。此外，这些MDS突变在HCT后即刻及之后超过1年的时间内均未检测到。这些数据支持了HCT后进行全面测序以检测供者来源恶性肿瘤的临床实用性，同时为dMDS在4年期间的克隆进展提供了见解。
