Homo sapiens Exome

"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."