Richard S. Houlston, M.D., Ph.D. Institute of Cancer Research (United Kindom)

THERAPY/ PROGNOSTIC

Identification of Germline Variants Influencing the Clinical Expression of Chronic Lymphocytic Leukemia

Grant awarded in 2006

Abstract:

The clinical behavior of chronic lymphocytic leukemia varies among patients. It is likely that part of the clinical difference is influenced by inherited genetic factors common in the population. We shall conduct a detailed analysis looking at variation in the human genome to tease out clinically useful markers of outcome. The identification of prognostic markers should allow for more accurate assessments and be helpful in the choice of therapeutic options. Specifically, these markers should allow for the prediction of likelihood of response and the potential of adverse reactions to chemotherapeutic treatments. This will allow patient-tailored decisions on drug selection and ultimately improvements in outcome.

We propose to conduct a genome-wide scan of single nucleotide polymorphisms (SNPs) to identify variants influencing the clinical behavior of CLL. The study will be based on an analysis of 10,000 non-synonymous SNPs (nsSNPs). SNPs alter the encoded amino acid sequence and have the potential to directly affect the function of expressed proteins, thereby providing a powerful strategy for identifying influential factors.

To generate unbiased findings we will analyse DNA from 400 patients entered into a large phase III trial (CLL4). The trial is comparing the purine analogue flurdarabine used alone or in combination with cyclophosphamide as a first-line treatment. Our analysis will examine the relationship between genotype and overall survival as well as the relationship between genotype and progression free survival, time to progression and toxicity.

Useful Definition:
single nucleotide polymorphisms (SNPs): a common DNA sequence variation among individuals that can help determine the likelihood that someone will develop a particular disease