Polymorphic variants of human DNA glycosylase NEIL2 and lung cancer susceptibilit

University Of Texas Med Br Galveston, Galveston TX

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Abstract

DESCRIPTION (provided by applicant): Although genetic predisposition and environmental factors such as exposure to genotoxic agents play critical etiological roles in many cancers, no gene yet has been identified as being directly responsible for the development of sporadic lung cell carcinoma. Unlike other internal organs, the lungs are continuously exposed to endogenous and exogenously generated oxidative stress, which is known to cause damage to various cellular macromolecules, including DNA. Oxidatively modified DNA bases are often mutagenic and/or toxic. These DNA base lesions are repaired primarily via the DNA base excision repair pathway. DNA repair gene mutations are likely to be involved in developing many sporadic cancers. We undertook a study aimed at identifying the genetic cause of lung cell carcinoma and investigated whether DNA repair gene variants play an etiological role in lung cancer initiation and development. We have found that downregulation of NEIL2, a recently identified oxidized base-specific DNA glycosylase, increases mutation frequency in the hprt gene of Chinese hamster V79 lung cell line as well as human lung cell line A549. These results prompted us to search for mutations at the NEIL2 locus in lung cancer patients (White). We identified four missense mutations in the coding regions of the NEIL2 gene;of these, two polymorphic variants (R103Q and R257L) were much more frequent (16%) in cancer patients than in normal, apparently healthy individuals (2-4%). We propose to advance our study by determining the prevalence of these variants in the other major ethnic groups (African American and Hispanics) as well and characterizing all these variants functionally. We will also generate Neil2-null mice to get insight into Neil2's role in protecting lung cancer. Thus a comprehensive biochemical analysis of wild-type vs. variant proteins along with cell biological and animal studies should give us insights into the molecular pathogenesis of lung cancer and NEIL2's likely etiological role in protecting against this disease. The central goal of our study is to translate basic knowledge of DNA repair and mutagenesis into practical approaches for assessing human risks associated with exposure to mutagenic agents in the environment. Successful completion of these studies will not only firmly establish the causal involvement of genetic mutation of DNA repair protein and the development of lung cancer but will also provide definitive insights for assessing human risks associated with exposure to various mutagens in the environment. Such basic knowledge could be exploited in developing therapeutic intervention strategies for lung cancer patients. PUBLIC HEALTH RELEVANCE: This study proposes to examine the role of a protein in repairing damage to DNA and its possible effect on cancer development. One phase is to develop a genetically altered mouse that does not produce this protein and study its potential to develop cancers. The second phase is to examine blood samples from lung cancer patients to determine if there are particular variants of this protein associated with this disease and if these variants are dysfunctional.