Project Overview

Precursor-B acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Despite improved treatment, hundreds still die annually and survivors often suffer long-term complications. Eighty percent of patients have large genetic alterations, yet these changes are not thought to cause ALL, and the remaining 20% have no identifiable genetic variation. Therefore, despite much research, the genetic cause as to why so many children develop ALL remains unknown. I believe that individual combinations of rare, inherited mutations predispose to developing ALL and modify response to therapy. We have recently published a powerful new DNA sequencing method that will comprehensively survey multiple genes in a rapid and cost-effective manner. In collaboration with the Children's Oncology Group (COG), I will use this method to sequence 56 genes involved in ALL development in the non-cancerous DNA from 96 children with high-risk ALL and 96 random children. These results will then be validated in a second cohort of 250 children with high-risk ALL.

Once the genetic changes are identified, I will study the functional impact of these mutations as well as review the treatment course of each patient to identify individual combinations of genetic variants that may have impacted ALL development or treatment. The COG can incorporate this cost-effective method into the next prospective ALL biology study. Understanding how rare variations impact ALL development and treatment will allow for better individual risk stratification and customized treatment which will minimize long-term complications and maximize the chance of a cure.