Homo sapiens Exome. Homo sapiens

"Children with Down syndrome (DS) and acute lymphoblastic leukaemia (ALL) have poorer survival and more relapses, than non-DS children with ALL, highlighting an urgent need for deeper mechanistic understanding of DS-ALL. Using full exome or cancer genes-targeted sequencing of 42 ALL samples from 39 DS patients, we uncover driver mutations in RAS (KRAS and NRAS) recurring to a similar extent (15/42) as JAK2 (12/42) mutations or P2RY8-CRLF2 fusions (14/42). RAS mutations were almost completely mutually exclusive with JAK2 mutations (p=0.016), driving a combined total of two thirds of analysed cases. Clonal architecture analysis revealed that both RAS and JAK2 drove sub-clonal expansions primarily initiated by CRLF2 rearrangements, and/or mutations in chromatin remodellers and lymphocyte differentiation factors. Remarkably, in 2/3 relapsed cases there was a switch from a primary JAK2 or PTPN11 mutated sub-clone to a RAS-mutated sub-clone in relapse. These results provide important new insights informing the patient stratification strategies for targeted therapeutic approaches for DS-ALL."

唐氏综合征（Down syndrome, DS）患儿合并急性淋巴细胞白血病（acute lymphoblastic leukaemia, ALL）的生存率显著低于非DS合并ALL的患儿，且复发率更高，这凸显了对DS-ALL开展深层次机制研究的迫切需求。本研究对39名DS患者的42份ALL样本实施全外显子组测序或癌症基因靶向测序，结果发现RAS家族（KRAS与NRAS）的驱动突变发生率（15/42）与JAK2突变（12/42）或P2RY8-CRLF2融合（14/42）相当。RAS突变与JAK2突变几乎完全互斥（p=0.016），二者合计覆盖了三分之二的分析病例。克隆结构分析显示，RAS与JAK2均可驱动亚克隆扩增，而此类扩增主要由CRLF2重排、染色质重塑因子突变及淋巴细胞分化因子突变启动。值得注意的是，3例复发病例中有2例出现了亚克隆类型转换：从原发性JAK2或PTPN11突变亚克隆转变为复发灶中的RAS突变亚克隆。本研究结果为DS-ALL的患者分层策略及靶向治疗方案提供了重要的新见解。