Investigating the Role of Genetic and Epigenetic Variation in Risk of Childhood Acute Lymphoblastic Leukemia in Down Syndrome

Background

Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood. Down syndrome (DS) is a genetic disorder caused by an extra chromosome 21, and DS children have a 20-fold increased risk of ALL. Furthermore, children with ALL and DS ("DS-ALL") have increased treatment-related deaths and disease recurrence than children without DS. Determining the cause of DS-ALL is, therefore, of paramount importance. The additional chromosome 21 must play a role in increased leukemia risk, but not every child with DS develops ALL. We predict that additional variations may affect DS-ALL risk.

Project Goal

This study is designed to discover why some children with DS contract leukemia while others do not. We will analyze genetic variation in DS-ALL children compared to DS children without ALL, specifically by investigating single base DNA changes as well as "copy number variation," that is, deleted or duplicated sections of DNA. This will be carried out across the genome, with a special focus on chromosome 21. We will also determine whether genetic variations are associated with ALL risk in children without DS, in a set of ALL cases and controls. Furthermore, we will assess how modifications of DNA expression that can turn genes on or off, so-called "epigenetic" changes, may affect DS-ALL risk.

This will be the first comprehensive investigation of the role of genetics and epigenetics in risk of DS-ALL, and will lead to earlier risk stratification and potentially improved treatment of this disease, as well as shedding light on the causes of ALL in all children.