Frequent cases of RAS-mutated Down syndrome acute lymphoblastic leukaemia lack JAK2 mutations

Abstract

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. Here, 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 are almost completely mutually exclusive with JAK2 mutations (P=0.016), driving a combined total of two-thirds of analysed cases. Clonal architecture analysis reveals 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 is 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.

Figure 1. Somatic mutations and CNAs in DS-ALLs.

Each column represents a tumour sample. Each line represents a cancer gene or a pathway. Grey cells with a symbol represent a somatic event in the corresponding gene. Coloured cells represent all cases with a somatic event in a pathway.

Figure 2. Clonal architecture analysis.

Percentage of reads from High Throughput Sequencing (HTS) supporting the somatic mutations in 43 studied DS-ALL samples. Colours represent different pathways. Symbols represent different driver genes. Horizontal bars represent half of fraction of blasts in the tumour sample.

Figure 3. Comparison of the somatic mutations between the primary leukaemias and relapses.

Pairwise comparisons of percentages of reads with the mutations and SCNAs between primary leukaemias and relapse samples for: 4-1036101 (a), 4-1036272 (b), 4-10 (c). Red dots are passenger mutations, and blue dots are the driver mutations. NB: for 4-10 only 387 cancer genes were sequenced. NB: In patients 4-1036272 and 4-10 P2RY8-CRLF2 rearrangement was persistent in primary leukaemia and relapse, please see Supplementary Figure 1 for an example.

Figure 4. Molecular multistep model of leuakemogeneis in DS-ALLs of BCP origin.

Green boxes depict the pathways and gene families involved in tumorigenesis. Percents of tumors with mutations in indicated pathways are given in parentheses.