Investigation of Causal Germline Mutations in High Hyperdiploid ALL

Background

High hyperdiploidy (HD) is the most common type of childhood acute lymphoblastic leukemia (ALL). Although relatively curable, the effects of chemotherapy last long into adulthood, leading to increased risk of heart disease, lung disease, secondary cancers and infertility. Further, around 10% of HD-ALL cases relapse and have poor survival, accounting for a large proportion of overall relapsed leukemias. There is strong evidence that the high hyperdiploidy event, which leads to an increase in the number of chromosomes in a cell, occurs prenatally. We also know that additional DNA mutations are required for full-blown leukemia. However, we do not understand what causes the initial hyperdiploidy event.

We have carried out a screening of DNA mutations in 57 cases of HD-ALL using next-generation sequencing and found a surprising number of mutations present in the germline, which may have caused the leukemia itself. In one gene of interest, which has not previously been associated with childhood ALL, we found mutations in 3 of 57 cases.

Project Goal

We wish to investigate this further by assessing the frequency of such mutations in a larger set of ALL cases and healthy controls to determine whether this gene is truly associated with risk of leukemia. This will require standard molecular laboratory methods as well as data analysis. Results from this project may help us to determine novel causes of childhood leukemia. In addition to a further understanding of the biology of the disease, this may lead to novel treatment options.