The risk of acute leukemia in Down syndrome (DS) (trisomy 21) is 20–30 times that of the general population. This increased risk relates both to acute lymphoblastic and acute myeloid leukemia (AML). The cumulative risk of leukemia in DS is 2.1 % by age of 5 years and 2.7 % by age of 30 years. The most common type is acute nonlymphocytic leukemia subtype M7- megakaryocytic leukemia, a type very rare in individuals with normal karyotypes. Acute megakaryoblastic leukemia (AMKL) is particularly prevalent, with an estimated 500-fold increased risk compared to the general population, and a transient form of AMKL, transient myeloproliferative disorder (TMD), is seen in about 10 % of newborn cases with DS, which usually resolves, but about 20 % will develop AMKL within the first 4 years of life (Hasle et al. 2000; Klusmann et al. 2007; Rabin and Whitlock 2009). Leukemia comprises about 60 % of all malignancies and 90 % of all childhood malignancies in DS. The standard incidence rate (SIR) for leukemia in DS is 56 at 4 years and 10 at 5–29 years of age. This risk is particularly pronounced for AML, usually early onset, 49 % developing below 1 year of age (Hasle 2001). AML-M after myelodysplastic syndrome is characteristic, as is trisomy 8 with reduced granulocyte lineage. Leukemic clones in DS are nearly always megaloblastic with GATA1 (zinc finger transcription factor required for erythroid and megakaryocytic development) mutations conferring a clonal advantage (Groet et al. 2003). Leukemic blasts in DS-AMKL harbor mutations in GATA1, which encodes a hematopoietic transcription factor. Most mutations cluster in exon 2 resulting in a truncated mutant protein, GATA1s, lacking the amino-terminal transcriptional activating domain. These mutations are also demonstrable at birth, thus representing an early intrauterine event, and a persistent subclone of TL cells may develop into AMKL as a result of additional mutations (Hitzler and Zipursky 2004).
There is an increased frequency of JAK2R683 mutations in acute lymphoblastic leukemia in Down syndrome. The overall occurrence of solid Tumours (especially breast cancer) in DS is reduced, except for retinoblastoma and germ cell Tumours (Look 2003).