PPM 04-0128-200014

Background: The germline polymorphisms in patients with Acute Lymphoblastic Leukemia (ALL) can alter the activity of drug metabolizing enzymes, drug transporters or targets influencing the efficacy and/or toxicity of antileukemic agents. These genetic variants could serve as biomarkers for toxicity and efficacy, allowing the identification of patients with modified sensitivity. The principle of personalized therapy, based on the identification of individual features associated with treatment response, aims to select adequate medications and their doses, in order to offer to patients the most effective treatment with the lower incidence of adverse events. For the pharmacological therapy of pediatric ALL, several examples of genetic polymorphisms affecting drug response and toxicity have been reported. However, despite the relatively large number of pharmacogenetic studies in the field, so far not many variants have been clinically integrated. The purine analog 6-mercaptopurine (6-MP) is a key medication for the successful treatment of childhood ALL, in particular for the consolidation and continuation therapies and is used in combination with the folate analog methotrexate (MTX). Genetic polymorphisms of thiopurine S-methyltransferase (TPMT) gene have been already demonstrated to influence mercaptopurine drug metabolism and its effects, representing one of the most studied and significant examples of associations between drug clinical effects and a genetic polymorphism and a paradigm of translation from bench to bedside. A number of variants have been annotated for other central medications during ALL treatment, such as MTX, Vincristine (VINC), L-asparaginase, steroids, etc.; however, meaningful implementation into the clinical practise is still lacking so far. Hypothesis: Based on published data, the overall profile of variations in drug metabolism genes in the Middle Eastern populations may be unique, implying that genetic associated toxicity induced by chemotherapy could be different from other more studied Western countries. We hypothesize that comprehensive sequencing of ALL pediatric patients supported by extensive data population obtained from the Qatar Genome Project (QGP), will allow us to correlate genetic variants with toxicity and efficacy profiling. Aims: In this study we aim at evaluating the pharmacogenetic profile of drugs (primarily 6-MP, MTX, secondarily VINC and steroids) commonly used in the treatment of pediatric ALL and to ideally define a set of relevant genes to be tested by the mean of high-throughput genotyping for ALL diagnosis in the Middle Eastern population. The project has the following specific objectives: Objective 1: Evaluate the pattern of genetic variation and the variants predicted pathogenicity of genes known to be implicated in the metabolism of drugs used in the ALL treatment regimens (primary targets: 6-MP, MTX; secondary targets: VINC, steroids) in a cohort of approximately 20,000 healthy Qatari people already sequenced at Sidra in the context of the QGP. Objective 2: Perform Whole Genome Sequencing (WGS) on 300 ALL subjects enrolled in Qatar and Lebanon in order to: • Evaluate the role of candidate gene variants on treatment toxicity and efficacy; • Discover novel variants associated with drug metabolism. Objective 3: Apply extensive epistatic approaches to drive the data analysis towards the potential identification of new genes and variants involved in drug hypersensitivity/toxicity. Objective 4: Develop a panel of genetic variations to be tested in ALL patients at diagnosis in the Middle East Region (clinical validation of the panel is not included in this research study). Study design: Over the 3-year tenure of this grant, as a first step, we will conduct a pharmacogenetic population study building on the huge dataset produced by the QGP, followed by comprehensive sequencing of ALL patients enrolled in Qatar and in Lebanon. To answer the above research questions, we will benefit from the unique expertise in genomic analyses and clinical knowledge available at Sidra and the collaboration with the Pharmacogenetics research lab and the Children's Cancer Center of Lebanon (CCCL) at the American University of Beirut. Expected project outcomes: Nowadays, in Qatar as well as in other Arab countries such as Lebanon, the treatment protocols currently in use are modeled after US and European clinical trials, in the absence of specific population characteristic data on pharmacogenomics profiles. We expect to gain a comprehensive understanding of the pharmacogenetic background for the main drugs used in ALL protocols, which could be instrumental in personalizing chemotherapy regimens for pediatric ALL in the Middle East. To our knowledge, this study represents the first attempt of this kind and depth, at whole genome level, in the Middle East.