Pharmacogenomics of childhood acute lymphoblastic leukemia (ALL)

Abstract

s3 Childhood ALL is a model for drug-responsive cancer: it is successfully cured with medications in 85%–90% of patients, but relapse remains unacceptably high for some subgroups, and therapy is complicated by the occurrence of adverse effects. Human germ-line genomic variability is common, with ∼1 in every 300 nucleotides (at least 10 million polymorphisms among humans) differing among individuals. Identifying the important genomic variants for purposes of optimizing anticancer therapy is the current challenge in cancer pharmacogenomics. Our research has been focused on elucidating the germ-line and acquired genomic variations that influence the effectiveness of and toxicity to chemotherapy regimens, with the long-term goal of individualizing therapy based on genetics to maximize cure and minimize toxicity. We and our many collaborators are pursuing candidate gene and whole genome approaches to this end, studying children enrolled on front-line ALL protocols at St. Jude and through the Children's Oncology Group. Based on these studies, candidate gene genotyping has been already incorporated into the treatment of childhood ALL and integrated with electronic medical records at St. Jude to optimize use of a few medications. This includes genetic testing for TPMT to adjust thiopurine doses and CYP2D6 to optimize use of codeine for vincristine neuropathy. Additional genotyping is conducted on a research basis and has identified SLCO1B1 as important for methotrexate disposition, IL15 as related to antileukemic drug response, ITPA as important for thiopurine toxicity, and a genomic basis to race-related differences in relapse risk. Gene expression analyses of ALL cells show expression signatures associated with resistance to chemotherapy and relapse. The principles and techniques of pharmacogenomics also have implications for adult malignancies. Because prognostic factors (including genomic variations) depend upon the details of therapy, collection of blood (for germ-line DNA) should be part of every cancer clinical trial to advance genomic research.