The latency between acquisition of an initiating somatic driver mutation by a single-cell and clinical presentation with cancer is largely unknown. We describe a remarkable case of monozygotic twins presenting with CALR mutation-positive myeloproliferative neoplasms (MPNs) (aged 37 and 38 years), with a clinical phenotype of primary myelofibrosis. The CALR mutation was absent in T cells and dermal fibroblasts, confirming somatic acquisition. Whole-genome sequencing lineage tracing revealed a common clonal origin of the CALR-mutant MPN clone, which occurred in utero followed by twin-to-twin transplacental transmission and subsequent similar disease latency. Index sorting and single-colony genotyping revealed phenotypic hematopoietic stem cells (HSCs) as the likely MPN-propagating cell. Furthermore, neonatal blood spot analysis confirmed in utero origin of the JAK2V617F mutation in a patient presenting with polycythemia vera (aged 34 years). These findings provide a unique window into the prolonged evolutionary dynamics of MPNs and fitness advantage exerted by MPN-associated driver mutations in HSCs.

单细胞获得起始体细胞驱动突变与癌症临床表现之间的潜伏期在很大程度上是未知的。我们描述了一个显着的同卵双胞胎病例，表现为CALR突变阳性骨髓增生性肿瘤 (MPN)（年龄分别为 37 岁和 38 岁），临床表型为原发性骨髓纤维化。T 细胞和真皮成纤维细胞中不存在CALR突变，证实了体细胞获得。全基因组测序谱系追踪揭示了CALR-突变的 MPN 克隆，发生在子宫内，随后是双胞胎到双胞胎的经胎盘传播和随后的类似疾病潜伏期。索引排序和单菌落基因分型显示表型造血干细胞 (HSC) 可能是 MPN 繁殖细胞。此外，新生儿血斑分析证实了真性红细胞增多症患者（34 岁）的JAK2V617F突变在子宫内的起源。这些发现为 MPN 的长期进化动态和 HSC 中 MPN 相关驱动突变所发挥的适应性优势提供了一个独特的窗口。