CYTOGENETIC AND MOLECULAR STUDIES OF DOWN-SYNDROME INDIVIDUALS WITH LEUKEMIA

There is an increased risk of leukemia in Down syndrome (DS) patients, with estimates ranging from 14 to 30 times the incidence rate observe d for chromosomally normal children. Furthermore, one type of leukemia , called ''transient leukemia'' (TL), occurs almost exclusively in DS infants. The basis of the association between DS and leukemia is unkno wn, but we and others have hypothesized that it may be influenced by t he mechanism of origin of the extra chromosome. Therefore, we initiate d a cytogenetic and molecular study of nondisjunction in leukemic DS i ndividuals. To date, we have obtained blood and/or tissue samples from 55 individuals consisting of 17 cases with TL, 7 cases of acute nonly mphocytic leukemia subtype M7 (ANLL-M7, or acute megakaryoblastic leuk emia, postulated to be related to TL), and 31 cases of other forms of leukemia. Analysis of these cases suggests differences between DS chil dren with TL and those with other types of leukemia or DS individuals with no history of leukemia. Specifically, the TL and ANLL-M7 cases ha ve a highly significant increase in the frequency of ''atypical'' cons titutional karyotypes (i.e., mosaic trisomies, rings, and/or isochromo somes) and are almost always male. Additionally, genetic mapping studi es suggest an increase in the frequency of disomic homozygosity, espec ially in proximal 21q, in DS individuals with TL and ANLL-M7.