Genetic Polymorphisms in UGT1A6 and UGT2B7 in Asian Population: Association With Lung Cancer Phenotype

Germline polymorphisms are inherited genetic variation present in all cells of the body. At molecular level, such variations may affect gene transcription, translation, mRNA stability, protein activity, protein expression (1-3). Mounting evidences have emerged showing that genetic polymorphisms in drug metabolizing genes and DNA repaired genes are major determinants of response to drugs and carcinogens with possible predictive or prognostic value for clinical outcome (4-6). However, only a small number of all polymorphisms discovered have functional significance and it is often difficult to predict this base on nucleotide sequence alone. Genome based studies have generated a wealth of data on genetic polymorphisms far exceeds our knowledge on the function of these variants. Hence, there is an urgent need to characterize the functional and expressional impact of genetic polymorphisms in candidate genes so that appropriate target polymorphisms most likely to affect the phenotype can be selected for larger scale association studies. In this study, we will adopt a novel 2-stage approach to identify and characterize new polymorphisms in the UGT1A6 and 2B7 genes in our Asian population. Data from our initial genotyping work will then be used to optimize the study design of the stage II association study for the generation of hypothesis that lung cancer histology (phenotype) is associated with UGT polymorphisms (genotype). This study will help to advance our understanding in the functional significance and diversity of genetic variants that exist in our population. It may also shed light on the role of UGT in carcinogenesis and will provide vital ground work for future studies of risk assessment, treatment and may allow identification of at risk individual for chemoprevention and adjuvant therapy studies.