Nasopharyngeal carcinoma (NPC) has a unique global distribution pattern -- Southeast Asia and some other localized regions of the eastern hemisphere that suggests the disease risk is driven by a combination of environmental exposures and specific genetic factors. Earlier studies have implicated many loci in various regions of the genome. Nevertheless, the implications of these associations remain enigmatic. Based on our preliminary results, we hypothesized that genetic variants and mutations in various DNA repair genes are associated with NPC. Further, we developed better informatics tools for analyzing DNA repair genes as a cluster. The results we obtained may provide new insights into the genetic determinants of NPC, and may possibly provide insights on genes contributing to risk for NPC and other diseases related to infections. What we learn from this study can also be applied to genetic research for other complex diseases including psychiatric disorders including schizophrenia, bipolar and autism. DNA repair plays a critical role in protecting against environmental carcinogenesis, and genetic variants of DNA repair genes have been reported to be associated with several human malignancies. To assess whether or not DNA repair gene variants are associated with nasopharyngeal carcinoma (NPC) risk, we conducted a pathway based candidate gene association study among the Cantonese population within the Guangdong Province, China. The study was conducted in two stages. In the discover stage, we investigated 676 SNPs (selected by an expert panel including Dr. Yao) which cover 88 DNA repair genes in a matched case-controls study in which 755 patients who were diagnosed of NPC and 755 community based health controls were included. We discovered that three genes, RAD51L1, BRCA2 and TP53BP1 were significantly involved in development of NPC. In the validation stage, we followed up the signals revealed in stage 1 and found that only two genetic variants in the RAD51L1 gene were significantly associated. The sample size of the validation was 1,558 cases and 1,297 controls. Furthermore, we conducted gene-environment interaction analysis. For the first time, we documented the exposure of cigarette smoking and salted fish consumption had significant interactions with the DNA repair gene variations with confidence. In this study, we utilize state-of-the-art, high-throughput genotyping methods as well as sophisticated methods of genetic analysis that take into account gene-gene interaction and gene-environment interactions in addition to single-SNP analyses. For example, we conducted innovative pathway based analysis such as CART. The CART method identified a subgroup with higher risk of NPC among the risk factors and the genetic variants of the Tp53BP1, RAD51, BRCA2 and MNAT1 genes. This interaction was confirmed by our own method. This finding indicated that smoking and variants in four genes may contribute jointly to the increased risk of NPC development. Within six months, we successfully identified genetic markers that help identify those at risk for NPC development. Our future work will focus on further validating this finding in a separate population and identifying genetic markers that effectively predict NPC outcome by combing the clinical samples used in stage I and stage II analysis. The combination of genetic and clinical information may be more predictive than either alone, potentially benefiting the treatment of NPC using appropriate methods.

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1
Fiscal Year
2011
Total Cost
$327,068
Indirect Cost
Name
U.S. National Institute of Mental Health
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