Gene signatures of 80 DS-ALL children were compared to those of 2,731 non-DS-ALL children, all of whom were enrolled in the Children’s Oncology Group (COG) P9900 treatment trial.9 Only 10% of DS-ALL children, compared to 48% of non-DS-ALL children, showed some of the favorable prognostic factors, ETV6-RUNX1 translocation (2.5% vs. 24%; P<0.001) and trisomies in chromosomes 4 and 10 (7.7% vs. 23.9%; P<0.001), normally seen in non-DS-ALL children. DS-ALL children showed a similar five-year overall survival (OS) rate as non-DS-ALL patients (86.7% vs. 85.4%; P=0.852), after excluding patients with favorable prognostic factors from analysis. In contrast, the inclusion of the remaining patients, with favorable prognostic factors, resulted in a lower five-year OS rate (85.8% vs. 90.0%; P=0.033) respectively. Low frequency and absence of favorable cytogenetics were suggested as a cause for lower survival rate in DS-ALL patients.9 Similarly, comprehensive genomic profiling studies by Loudin et al.,10 in 58 DS-ALL and 68 non-DS-ALL cases detected a novel somatic 33.8-kb deletion in the 6p22 histone gene cluster region in 11 (22%) DS-ALL cases. Patients with homozygous deletion in the gene cluster region showed high methylation of 109 genes. High methylation results in lowered gene expression of transcription factors involved in cell proliferation, suggesting an alternate mechanism of DS-ALL progression.10

A novel mutated oncogene, TRIB1, has been identified in one case of DS-AMKL.11 The relevance of TRIB1 is understood from its mutated status in the patient where GATA1 was absent, suggesting a possible multistep pathway to leukemogenesis.11 The RAS pathway has also been implicated in DS-AML leukemogenesis in a study by Blink et al. Pediatric AML cases can be classified as Type I aberrations that promote unproliferated cell growth, and Type II aberrations, which result in aberrant cell differentiation. Novel cryptic translocations (e.g., NUP98-NSD1) and mutations in genes such as WT1, CEBPA and FLT3 distinguish Type I and Type II pediatric AML cancers. The authors investigated the same gene signature in 34 DS-AML patients. Mutations in 7% of patients were found specifically in genes associated with the RAS pathway. There were single nucleotide polymorphisms (SNP) in the WT1 and IDH1 genes. Type I and Type II aberrations were absent in the DS-AML cohort, indicating a distinct gene signature compared to non-DS AML cancer.12


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Identifying new pathways of cancer
Research carried out by Mullighan et al.5 demonstrated the interaction between several mutated genes. The study analyzed 272 children with B-progenitor ALL, which included 22 children with DS. It was found that 54.5% of DS-ALL children had deletion in the PAR1 gene.5 The mutant PAR1 gene causes the fusion of P2RY8 and CRLF2, where CRLF2 comes under the control of the P2RY8 promoter. CRLF2 is over-expressed, and is a receptor for a cytokine, thymic stromal lymphopoietin (TSLP), which regulates the development of T-lymphocytes.13 A second mutation in JAK2 observed in 27.2% of DS-ALL children results in kinases being indefinitely expressed causing uncontrolled cell proliferation. The rate of co-occurrence of PAR1 deletion with JAK2 was 27.6%, and functional analyses in cell lines suggested a synergistic effect on leukemogenesis.5

Hertzberg et al., in a parallel study, demonstrated the identical interaction between CRLF2 over-expression and JAK2 genes in cell lines, resulting in aberrant cell proliferation. Thirty-three of 53 DS-ALL patients (62.3%) over-expressed CRLF2. DS-ALL children diagnosed with increased/moderate expression of CRLF2 were younger than non-DS-ALL children (5.56 vs. 9.87 years, P=0.004). Ten of the DS-ALL patients over-expressing CRLF2 also had a somatic mutation in JAK2.4 Ensor et al. showed that CRLF2 over-expression alone was not indicative of poor outcome in DS-ALL. Incidence of P2RY8-CRLF2 was shown to be predominant in DS-ALL (n=43 vs. n=9), and cases were younger than those with interstitial deletion, IGH-CRLF2 (4 vs. 8 years). The study suggests further analyses of the association of CRLF2 with other genetic mutations to determine the effect on survival.14