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Development and application of DNA damage and DNA repair capacity indices to prostate cancer.


Description

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment and several of the compounds in its class are known carcinogens. However, the cellular response to PAH exposure is complex. Polymorphisms in metabolizing and conjugating genes may modify the level of DNA damage resulting from the direct (DNA adducts) and indirect (oxidized DNA bases) action by PAHs. In addition, polymorphisms in DNA repair genes may alter an individual's ability to repair this damage. Evaluation of the association between prostate cancer and factors involved in PAH metabolism, conjugation and DNA repair using conventional "one-at-a-time" approaches has produced equivocal findings. Furthermore, although quantitative kinetic models have been attempted, the pathways involved in the cellular response to PAHs and their interrelations remain incompletely characterized in humans, restricting accurate construction of gene regulatory networks. In an attempt to overcome these current methodological limitations, we present an approach that allows for the simultaneous evaluation of multiple sources of PAHs and key candidate genes (single nucleotide polymorphisms, SNPs) involved in PAH metabolism, conjugation and DNA repair pathways. This approach uses hierarchical latent variable path analysis (HLVPA) to generate DNA Damage from PAHs and DNA Repair Capacity Indices (composite scores)