Acquired Genetic Abnormalities in Acute Lymphoblastic Leukaemia in Patients with Down Syndrome.

Children with Down syndrome (DS) have a 30 fold increased risk of developing leukaemia compared to their non-DS counterparts. While it is now known that cooperating mutations in the haemopoietic transcription factor GATA1 occur in all cases of acute megakaryoblastic leukaemia in Down syndrome patients, the additional genetic events which confer an increased risk of acute lymphoblastic leukaemia in Down syndrome (ALL-DS) are unknown. We initiated a search for mutations in the coding region of candidate genes including RAS, B-RAF, FLT3, KIT and JAK2 in a series of ALL-DS cases. No mutations were identified. We then carried out high resolution (Affymetrix 250K Nsp and 250K Sty) SNP array analysis of leukaemic blast cell DNA from 9 cases of ALL-DS, the majority of which had matched remission DNA. Overall, the whole and partial chromosome gains and losses were in agreement with the karyotype, but in all cases these were updated and refined. There were between 1 and 12 additional copy number alterations per case, with small focal deletions comprising 1 or 2 genes being more frequent than gains. The most common of these was a focal deletion of the CDKN2A gene (4 cases), all of which had either a partial deletion or copy number neutral LOH of the whole of 9p. The other most common focal deletions were of 12p13.3 (ETV6 gene) and 9p13.2 (PAX5), found in 2 cases each. Other regions affected included 3q13.2 (BTLA), 5q33.3 (EBF1), 13q14.2 (RB1) and 20p12.2 (including c20orf94), identified in 1 case each. These results indicate that the secondary genetic events in ALL-DS are similar to those for ALL overall (