ZIA BC 011495 (ZIA) | |||
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Title | Integrative Molecular Epidemiology of Human Cancer | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Harris, Curtis | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $1,214,304 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (20.0%) Inflammatory Bowel Disease (20.0%) |
Colon/Rectum (20.0%) Lung (80.0%) |
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Research Type | |||
Interactions of Genes and/or Genetic Polymorphisms with Exogenous and/or Endogenous Factors Resources and Infrastructure Related to Detection, Diagnosis, or Prognosis |
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Abstract | |||
Project 2A: Evaluate the functional importance of gene and gene-environment interactions in the molecular epidemiology and cancer-related disparities between African- and European-Americans. Genome Wide Association Studies (GWAS) of African-American lung cancer will identify potential functional polymorphisms involved in health disparities. African-American men have higher age-adjusted cancer incidence rates (99.9 per 100,000) when compared with Caucasian and Asian men (76.4 and 52.2 per 100,000, respectively), as well as higher age-adjusted death rates (African American 82.6 per 100,000; Caucasian 65.3 per 100,000; Asian 35.9 per 100,000). To date, GWAS performed in populations of European and Asian descent have identified over 15 lung cancer risk loci. Although African Americans have higher lung cancer incidence and poorer lung cancer survival when compared with other racial and ethnic populations in the United States, no GWAS has been conducted in this population. In addition, African admixture in African Americans could provide an opportunity to identify new lung cancer risk alleles. In light of the current evidence suggesting a genetic contribution to lung cancer in African Americans, we initiated and conducted a first-in-kind two-stage GWAS, genotyping 1,024,001 single nucleotide polymorphisms (SNPs) in 1737 cases and 3602 controls (stage 1), followed by replication of the most significantly associated genotypes in an independent sample set of 866 cases and 796 controls (stage 2). Both stages of the study included samples from the NCI-MD case-control cohort, in addition to 10 other cohorts. Combining results from stages 1 and 2, two SNPs were significant at the genome-wide significance level, rs2036527, adjacent to CHRNA5. We confirmed previous results for two loci associated with lung cancer on 15q25.1 and 5p15.33, near candidate genes, CHRNA5 and TERT, respectively, in African Americans. Project 2B: Functional polymorphisms in microRNA, and their mRNA Targets are associated with lung cancer risk, diagnosis and prognosis. MicroRNAs (miRNA), a class of noncoding genes, modulate mRNA translation by primarily binding to the 3primeUTR of mRNA transcripts. MiRNAs temper the translation of up to 60% of mRNA transcripts through semiconservative binding. The seed region of a miRNA, which corresponds to nucleotides 2-8 from its 5 prime end, coordinates exact Watson-Crick binding to the target mRNA sequence. Genetic variation within a miRNA-binding site has two main consequences on target protein expression, i.e., quantitative and qualitative. Requirements for sequence complementarity and stable thermodynamics around the miRNA-3 prime UTR seed-binding site primes sequence variations within these regions as strong candidates for functional SNPs, thus we hypothesized that genetic variation in miRNA-binding sites is a contributing factor to lung cancer risk. We analyzed several key biologic pathways previously implicated in lung cancer etiology; Phase I/II metabolism, DNA repair, and inflammation. Initial genotyping was conducted on patients and population controls from the NCI-MD case-control study, followed by validation on a case-control series from our Japanese collaborators. rs1126579, in CXCR2, was found to be associated with a reduced risk of lung cancer in European Americans and in the Japanese population in adjusted models. Consistent with our bioinformatics prediction, we subsequently showed that rs1126579 disrupts a binding site for miR516a-3p and alters expression of CXCR2. We leveraged TCGA RNA-seq data to explore if CXCR2 isoforms are differentially modulated by rs1126579. We found expression of CXCR2 - UC002vha.1 to be higher in samples with T allele compared with C allele. Collectively, these data suggest that T allele increases CXCR2 expression in lung tissue by disrupting a binding site for miR-516a-3p. Consistent with the association of the T allele with reduced risk, loss of miRNA regulation and higher expression |