Genomics of ALL in children with Down syndrome

Almost all cases of ALL in children with Down syndrome are B-ALL. T-ALL is uncommon.

The common recurring genomic alterations found in non-Down syndrome ALL (e.g., high hyperdiploidy and ETV6::RUNX1) occur much less often in children with Down syndrome and ALL. Other alterations occur more often in children with Down syndrome and ALL.

Fifty percent to 60% of children with Down syndrome and ALL have CRLF2 rearrangements involving either IGH or P2RY8, with most cases (85%) involving P2RY8.

Fifty percent to 60% of children with Down syndrome and ALL have CRLF2 rearrangements involving either IGH or P2RY8, with most cases (85%) involving P2RY8.

Approximately one-half of CRLF2-rearranged cases have JAK2 variants, which are not seen in children with Down syndrome and ALL who do not have CRLF2 rearrangements.

Fifty percent to 60% of children with Down syndrome and ALL have CRLF2 rearrangements involving either IGH or P2RY8, with most cases (85%) involving P2RY8.

IKZF1 alterations occur in approximately 30% of cases with CRLF2 rearrangements but in only approximately 10% of cases without CRLF2 rearrangements.

Fifty percent to 60% of children with Down syndrome and ALL have CRLF2 rearrangements involving either IGH or P2RY8, with most cases (85%) involving P2RY8.

Twenty-five percent of CRLF2-rearranged cases in patients with Down syndrome are classified by gene expression as BCR::ABL1-like, compared with 54% of CRLF2-rearranged non-Down syndrome ALL cases.

Fifty percent to 60% of children with Down syndrome and ALL have CRLF2 rearrangements involving either IGH or P2RY8, with most cases (85%) involving P2RY8.

Overall, patients with CRLF2-rearranged ALL and Down syndrome have an intermediate prognosis. However, patients with a BCR::ABL1-like gene expression signature have worse outcomes than those without a BCR::ABL1-like gene expression signature and CRLF2 rearrangements (EFS rates, 39.5% ± 8.1% vs. 82% ± 4.4%; OS rates, 70.3% ± 8.7% vs. 86.9% ± 4.8%).

The IGH::IGF2BP1 gene fusion occurs in approximately 3% of patients with Down syndrome. This gene fusion is rare in patients with ALL who do not have Down syndrome. In one retrospective analysis, this fusion was associated with a relatively favorable outcome (EFS rate, 87.5% ± 11.7%).

C/EBP altered (C/EBPalt) B-ALL, which is characterized by aberrant activation of C/EBP family genes, is also markedly enriched in children with Down syndrome (10.5% of Down syndrome ALL vs. 0.1% of non-Down syndrome B-ALL).

C/EBP altered (C/EBPalt) B-ALL, which is characterized by aberrant activation of C/EBP family genes, is also markedly enriched in children with Down syndrome (10.5% of Down syndrome ALL vs. 0.1% of non-Down syndrome B-ALL).

Rearrangements of CEBPD are the most common C/EBPalt lesion, occurring in 7.5% of Down syndrome ALL cases. The fusion partner for more than 80% of CEBPD rearrangements is IGH. Less common fusion partners include MME, TPM4, 9p13.2, and 6q25.3.

C/EBP altered (C/EBPalt) B-ALL, which is characterized by aberrant activation of C/EBP family genes, is also markedly enriched in children with Down syndrome (10.5% of Down syndrome ALL vs. 0.1% of non-Down syndrome B-ALL).

Another 4% to 5% of Down syndrome ALL is characterized by alterations in other C/EBP family members, such as CEBPA and CEBPE.

C/EBP altered (C/EBPalt) B-ALL, which is characterized by aberrant activation of C/EBP family genes, is also markedly enriched in children with Down syndrome (10.5% of Down syndrome ALL vs. 0.1% of non-Down syndrome B-ALL).

C/EBPalt cases commonly harbor concomitant variants of FLT3, KDM6A, and SETD2.

C/EBP altered (C/EBPalt) B-ALL, which is characterized by aberrant activation of C/EBP family genes, is also markedly enriched in children with Down syndrome (10.5% of Down syndrome ALL vs. 0.1% of non-Down syndrome B-ALL).

C/EBPalt was associated with high rates of MRD-negative remission at the end of induction therapy (87.1%) and an intermediate outcome (10-year EFS rate, 73.9% ± 9.9%; 10-year OS rate, 76.7% ± 12.8%).